Major Project On Novel Approach For The Cure of Aids

A REVIEW ON
“NOVEL APPROACH FOR THE CURE OF AIDS”

A
Major Project Submitted to
Chhattisgarh Swami Vivekanand Technical University, Bhilai
In Partial Fulfilment of the requirement for the degree
Of
Bachelor of Pharmacy
CHHATTISGARH SWAMI VIVEKANAND TECHNICAL

UNIVERSITY, BHILAI
Submitted By;
Supervised By;
Miss Kritika Kanoujia
Miss Sonam Soni
Roll no. 3724114087
B.Pharma 8th Sem
RUNGTA COLLEGE OF PHARMACEUTICAL SCIENCE &

RESEARCH, KOHKA-KURUD ROAD, BHILAI
(2017-18)
DECLARATION
I hereby declare that this major project titled A Review on "NOVEL APPROACH FOR
THE CURE OF AIDS" prepared under the guidance of Miss Sonam Soni, Faculty of
Rungta College of Pharmaceutical Science and Research, Kohka-Kurud Road, Bhilai (C.G).
The same is submitted to CHHATTISGARH SWAMI VIVEKANAND TECHNICAL
UNIVERSITY, BHILAI (C.G.) for partial fulfillment of the requirement for the degree of
Bachelor of Pharmacy.
I further declare that I have not submitted this major project previously for award of any
degree to me.
Date: Kritika Kanoujia

Place: Bhilai
CERTIFICATE
This is to certify that Miss Kritika Kanoujia, Student of B.Pharmacy 8th Semester, Enrollment
No. AO8124, Roll No. 3724114087, of Rungta College of Pharmaceutical Science and
Research Kohka-Kurud Road, Bhilai, has submitted her major project entitled A Review on
"NOVEL APPROACH FOR THE CURE OF AIDS" for the partial fulfilment of the
requirement for the Degree of Bachelor of Pharmacy. She has completed her project under
the supervision of Miss Sonam Soni. Her work is original, satisfactory and is not submitted
anywhere else for the requirement of any degree.
I hereby forward her major project for the Bachelor degree in Pharmacy during the academic
session 2017-18.
SUPERVISOR PRINCIPAL
Miss Sonam Soni Dr. D. K. Tripathi
ACKNOWLEDGEMENT
I owe my deep sense of gratitude to my respected supervisor Miss Sonam Soni, Department
of Rungta College of Pharmaceutical Science and Research, Kohka-Kurud road, Bhilai
(C.G.) for her meticulous and expert guidance, constructive criticism, and benevolent
behavior throughout my ordeal of the present review article. I shall remain grateful to her for
her cordial, cooperative attitude, wise and knowledgeable counsel that acted as an impetus in
the successful completion of my project work.
My heartfelt thanks to our respected Principal, Dr. D.K. Tripathi, for providing us the
opportunity to such a great literature survey.
At last I thank to each and everyone who has helped me in a direct or indirect manner for
completion of this literature survey.
Kritika Kanoujia
CONTENTS
S.NO. TITLE PAGE NO.
1. INTRODUCTION 6-7
2. HISTORY 7-8
3. AIDS (ACQUIRED IMMUNODEFICIENCY SYNDROME) 8
4. ABOUT HIV 8-9

STRUCTURE AND GENOME
5. 9-10
ORIGINS
6. 11-12
HIV TROPISM AND GENETIC VARIABILITY
7. 12-14
METHODS OF HIV TRANSMISSION
8. 14-15
9. STAGES OF HIV INFECTION 16
10. SYMPTOMS OF HIV INFECTION 16-18
11. PATHOPHYSIOLOGY OF HIV INFECTION 18-23

THE BERLIN PATIENT
12. 23
13. CURRENT HIV/AIDS TREATMENT 24
14. ANTIRETROVIRAL THERAPY (ART) 24-27
15. TOWARDS A CURE 27
16. APPROACH 27
17. CONCLUSION 27
18. REFERENCES 28-31

Novel Approach for the cure of AIDS
INTRODUCTION
Acquired immunodeficiency syndrome (AIDS) is a medical condition caused by the human
immunodeficiency virus (HIV). HIV infection is a very current threat and can easily be termed
as a curse upon the human race. The scientific community first noticed and recognized the
presence of AIDS as an actual disease following an increase in the incidence of very rare
opportunistic infections and cancers among otherwise healthy homosexual men . The global
prevalence of HIV has expanded since its discovery and has now spread across the globe
despite advances in antiretroviral treatments (ART). The mortality and morbidity rates
related to HIV infections remain high in developing countries largely due to food insecurity
and malnutrition . Long-term concomitant sexual relationships and high infectivity during
the early phase of HIV infections are other factors behind the extensive spread of HIV in the
general population. The emergence of AIDS was first reported in 1981 followed by the
identification of HIV as the cause of the disease in 1983. HIV/AIDS is now a global pandemic
that has become the leading infectious killer of adults worldwide . By 2006, more than 65
million people had been infected with the HIV virus worldwide and 25 million had died of
AIDS . At the end of 2007, around 33 million people were living with the virus, with 2.7
million new infections and 2 million deaths each year . This has caused tremendous social
and economic damage worldwide, with developing countries, particularly Sub-Saharan
Africa, heavily affected. More than 75 million people worldwide have been infected with
human immunodeficiency virus (HIV), and there are now approximately 37 million
individuals living with the infection. Untreated HIV replication causes progressive CD4 + T
cell loss and a wide range of immunological abnormalities, leading to an increased risk of
infectious and oncological complications. HIV infection also contributes to cardiovascular
disease, bone disease, renal and hepatic dysfunction and several other common
morbidities. Antiretroviral drugs are highly effective at inhibiting HIV replication, and for
individuals who can access and adhere to these drugs, combination antiretroviral therapy
leads to durable (and probably lifelong) suppression of viral replication. Viral supp ression
enables immune recovery and the near elimination of the risk for developing acquired
immune deficiency syndrome (AIDS). Despite effective treatment, HIV-infected
individuals have a higher than expected risk of heart, bone, liver, kidney and neurolo gical
disease. When used optimally by an infected (or by an uninfected) person, antiretroviral
drugs can virtually eliminate the risk of HIV transmission. Despite major advances in
prevention sciences, HIV transmission remains common in many vulnerable populations,
including men who have sex with men, injection drug users and sex workers. Owing to a
lack of widespread HIV testing and the costs and toxicities associated with antiretroviral
drugs, the majority of the infected population is not on effective antiretroviral therapy.
To reverse the pandemic, improved prevention, treatment and implementation
approaches are necessary.
A cure for HIV/AIDS has been elusive in almost 30 years of research. Early treatments
focused on antiretroviral drugs that were effective only to a certain degree. The first drug,
zidovudine, was approved by the US FDA in 1987, leading to the approval of a total of 25
drugs to date, many of which are also available in fixed-dose combinations and generic
formulations for use in resource-limited settings (to date, only zidovudine and didanosine
are available as true generics in the USA). However, it was the advent of a class of drugs
known as protease inhibitors and the introduction of triple-drug therapy in the mid-1990s
that revolutionized HIV/AIDS treatment. This launched the era of highly active antiretroviral
Rungta College of Pharmaceutical Science and Research (2017-2018) Page 6

therapy (HAART), where a combination of three or more different classes of drugs are
administered simultaneously. The use of the HAART regimen, particularly in the developed
world, has resulted in tremendous success in improving the expectancy and quality of lives
for patients . However, some HAART regimens have serious side effects and, in all cases,
HAART has to be taken for a lifetime, with daily dosing of one or more pills. Some patients
also develop resistance to certain combinations of drugs, resulting in failure of the
treatment. The absence of complete cure under current treatment underscores the great
need for continued efforts in seeking innovative approaches for treatment of HIV/AIDS.
The development of potent antiretroviral therapy (ART) for the treatment of human
immunodeficiency virus (HIV) infection has been one of the greatest advances in modern
medicine. While therapy has become increasingly easy to take and well tolerated, there
remain limitations that prevent some patients from benefiting from treatment. Future goals
of therapy are to overcome the limitations of current treatment, including side effects and
the need to take medication on a daily basis.
Early versions of potent ART that were able to suppress HIV to undetectable levels consist of
regimens that included two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a
protease inhibitor (PI) or a non-NRTI (NNRTI), often requiring relatively frequent dosing, had
substantial side effects, frequent drug-drug and drug-food interactions, and at times were
associated with a high risk of virologic failure and emergent drug-resistant virus. The next
few decades of drug development focused on overcoming these limitations of treatment.
Initial success included the use of pharmacologically boosted PIs that were easier to take,
had fewer drug-food interactions, and were rarely associated with the emergence of drug-
resistant virus. In addition, dosing frequency was simplified, ultimately to once-daily
regimens. Simultaneously, there was the emergence of new NRTIs that were given as fixed-
dose combinations once daily and associated with less toxicity. The next major advance in
treatment was the development of a new class of therapy, integrase strand transfer
inhibitors (INSTIs). Overriding all of these advances was the emergence of increasing
numbers of fixed-dose combinations, including regimens that could be given as a single pill
once per day.
HISTORY
AIDS was first clinically observed in 1981 in the United States. The initial cases were a cluster
of injection drug users and gay men with no known cause of impaired immunity who
showed symptoms of Pneumocystis carinii pneumonia (PCP), a rare opportunistic infection
that was known to occur in people with very compromised immune systems. Soon
thereafter, additional gay men developed a previously rare skin cancer called Kaposi's
sarcoma (KS). Many more cases of PCP and KS emerged, alerting U.S. Centers for Disease
Control and Prevention (CDC) and a CDC task force was formed to monitor the
outbreak. The earliest retrospectively described case of AIDS is believed to have been in
Norway beginning in 1966.
In the beginning, the CDC did not have an official name for the disease, often referring to it
by way of the diseases that were associated with it, for example, lymphadenopathy, the
disease after which the discoverers of HIV originally named the virus. They also
used Kaposi's Sarcoma and Opportunistic Infections, the name by which a task force had

been set up in 1981. In the general press, the term GRID, which stood for gay-related
immune deficiency, had been coined. The CDC, in search of a name, and looking at the
infected communities coined "the 4H disease", as it seemed to single out homosexuals,
heroin users, haemophiliacs, and Haitians. However, after determining that AIDS was not
isolated to the gay community, it was realized that the term GRID was misleading
and AIDS was introduced at a meeting in July 1982. By September 1982 the CDC started
using the name AIDS.
In 1983, two separate research groups led by American Robert Gallo and French
investigators Françoise Barré-Sinoussi and Luc Montagnier independently declared that a
novel retrovirus may have been infecting AIDS patients, and published their findings in the
same issue of the journal Science. Gallo claimed that a virus his group had isolated from a
person with AIDS was strikingly similar in shape to other human T-lymphotropic
viruses (HTLVs) his group had been the first to isolate. Gallo's group called their newly
isolated virus HTLV-III. At the same time, Montagnier's group isolated a virus from a patient
presenting with swelling of the lymph nodes of the neck and physical weakness, two classic
symptoms of AIDS. Contradicting the report from Gallo's group, Montagnier and his
colleagues showed that core proteins of this virus were immunologically different from
those of HTLV-I. Montagnier's group named their isolated virus lymphadenopathy-
associated virus (LAV). As these two viruses turned out to be the same, in 1986 LAV and
HTLV-III were renamed HIV.
Another group working contemporaneously with the Montagnier and Gallo groups was that
of Dr. Jay Levy at the University of California, San Francisco. He independently discovered
the AIDS virus in 1983 and named it the AIDS associated retrovirus (ARV). This virus was very
different from the virus reported by the Montagnier and Gallo groups. The ARV strains
indicated, for the first time, the heterogeneity of HIV isolates and several of these remain
classic examples of the AIDS virus found in the United States.
AIDS (ACQUIRED IMMUNODEFICIENCY SYNDROME)

AIDS is a disease of the immune system due to infection with HIV. HIV destroys the CD4 T
lymphocytes (CD4 cells) of the immune system, leaving the body vulnerable to life-
threatening infections and cancers. Acquired immunodeficiency syndrome (AIDS) is the
most advanced stage of HIV infection. . HIV attacks the immune system by destroying CD4+
T cells, a type of white blood cell that is vital to fighting off infection. The destruction of
these cells leaves people living with HIV vulnerable to other infections, diseases and various
complications.
ABOUT HIV
HIV is a member of the genus Lentivirus, part of the family Retroviridae. Lentiviruses have
many morphologies and biological properties in common. Many species are infected by
lentiviruses, which are characteristically responsible for long-duration illnesses with a
long incubation period. Lentiviruses are transmitted as single-stranded, positive-
sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNA genome is
converted (reverse transcribed) into double-stranded DNA by a virally encoded

enzyme, reverse transcriptase, that is transported along with the viral genome in the virus
particle. The resulting viral DNA is then imported into the cell nucleus and integrated into
the cellular DNA by a virally encoded enzyme, integrase, and host co-factors. Once
integrated, the virus may become latent, allowing the virus and its host cell to avoid
detection by the immune system, for an indiscriminate amount of time. The HIV virus can
remain dormant in the human body for up to ten years after primary infection; during this
period the virus does not cause symptoms. Alternatively, the integrated viral DNA may
be transcribed, producing new RNA genomes and viral proteins, using host cell resources,
that are packaged and released from the cell as new virus particles that will begin the
replication cycle anew.
Two types of HIV have been characterized:
HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both LAV
(Lymphadenopathy Associated Virus) and HTLV-III (Human T cell Lymphotropic Virus III).
HIV-1 is more virulent and more infective than HIV-2, and is the cause of the majority of HIV
infections globally. The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of
those exposed to HIV-2 will be infected per exposure. Due to its relatively poor capacity for
transmission, HIV-2 is largely confined to West Africa.
STRUCTURE AND GENOME
HIV is different in structure from other retroviruses. It is roughly spherical with a diameter
of about 120 nm, around 60 times smaller than a red blood cell. It is composed of two
copies of positive-sense single-stranded RNA that codes for the virus's nine genes enclosed
by a conical capsid composed of 2,000 copies of the viral protein p24.The single-stranded
Fig 1: Structure of HIV

RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the
development of the virion such as reverse
transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein
p17 surrounds the capsid ensuring the integrity of the virion particle.

This is, in turn, surrounded by the viral envelope, that is composed of the lipid bilayer taken
from the membrane of a human host cell when the newly formed virus particle buds from
the cell. The viral envelope contains proteins from the host cell and relatively few copies of
the HIV Envelope protein, which consists of a cap made of three molecules known
as glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the
structure into the viral envelope. The Envelope protein, encoded by the HIV env gene,
allows the virus to attach to target cells and fuse the viral envelope with the target cell's
membrane releasing the viral contents into the cell and initiating the infectious cycle.
As the sole viral protein on the surface of the virus, the Envelope protein is a major target
for HIV vaccine efforts. Over half of the mass of the trimeric envelope spike is N-
linked glycans. The density is high as the glycans shield the underlying viral protein from
neutralisation by antibodies. This is one of the most densely glycosylated molecules known
and the density is sufficiently high to prevent the normal maturation process of glycans
during biogenesis in the endoplasmic and Golgi apparatus. The majority of the glycans are
therefore stalled as immature 'high-mannose' glycans not normally present on human
glycoproteins that are secreted or present on a cell surface. The unusual processing and
high density means that almost all broadly neutralising antibodies that have so far been
identified (from a subset of patients that have been infected for many months to years) bind
to or, are adapted to cope with, these envelope glycans.
The molecular structure of the viral spike has now been determined by X-ray
crystallography and cryo-electron microscopy. These advances in structural biology were
made possible due to the development of stable recombinant forms of the viral spike by the
introduction of an intersubunit disulphide bond and an isoleucine to proline mutation in
gp41.The so-called SOSIP trimers not only reproduce the antigenic properties of the native
viral spike but also display the same degree of immature glycans as presented on the native
virus. Recombinant trimeric viral spikes are promising vaccine candidates as they display less
non-neutralising epitopes than recombinant monomeric gp120, which act to suppress the
immune response to target epitopes.
The RNA genome consists of at least seven structural landmarks (LTR, TAR, RRE, PE, SLIP,
CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a
tenth tev, which is a fusion of tat, env and rev), encoding 19 proteins. Three of these
genes, gag, pol, and env, contain information needed to make the structural proteins for
new virus particles. For example, env codes for a protein called gp160 that is cut in two by a
cellular protease to form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr,
and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the
ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.
The two Tat proteins (p16 and p14) are transcriptional transactivators for the LTR promoter
acting by binding the TAR RNA element. The TAR may also be processed into microRNAsthat
regulate the apoptosis genes ERCC1 and IER3. The Rev protein (p19) is involved in shuttling
RNAs from the nucleus and the cytoplasm by binding to the RRE RNA element. The Vif
protein (p23) prevents the action of APOBEC3G (a cellular protein that deaminates Cytidine
to Uridine in the single stranded viral DNA and/or interferes with reverse transcription).
The Vpr protein (p14) arrests cell division at G2/M. The Nef protein (p27) down-
regulates CD4 (the major viral receptor), as well as the MHC class I and class IImolecules.

Nef also interacts with SH3 domains. The Vpu protein (p16) influences the release of new
virus particles from infected cells. The ends of each strand of HIV RNA contain an RNA
sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control
production of new viruses and can be triggered by proteins from either HIV or the host cell.
The Psi element is involved in viral genome packaging and recognized by Gag and Rev
proteins. The SLIP element (TTTTTT) is involved in the frameshift in the Gag-Pol reading
frame required to make functional Pol.
ORIGINS
Both HIV-1 and HIV-2 are believed to have originated in non-human primates in West-
central Africa, and are believed to have transferred to humans (a process known
as zoonosis) in the early 20th century.
HIV-1 appears to have originated in southern Cameroon through the evolution of SIV(cpz),
a simian immunodeficiency virus (SIV) that infects wild chimpanzees (HIV-1 descends from
the SIV(cpz) endemic in the chimpanzee subspecies Pan troglodytes troglodytes). The
closest relative of HIV-2 is SIV (smm), a virus of the sooty mangabey(Cercocebus atys atys),
an Old World monkey living in littoral West Africa (from southern Senegal to western Côte
d'Ivoire). New World monkeys such as the owl monkey are resistant to HIV-1 infection,
possibly because of a genomic fusion of two viral resistance genes. HIV-1 is thought to have
jumped the species barrier on at least three separate occasions, giving rise to the three
groups of the virus, M, N, and O.
Left to right: the African green

monkey source of SIV, the sooty
mangabey source of HIV-2, and
the chimpanzee source of HIV-1
There is evidence that humans who participate in bushmeat activities, either as hunters or
as bushmeat vendors, commonly acquire SIV. However, SIV is a weak virus, and it is typically
suppressed by the human immune system within weeks of infection. It is thought that
several transmissions of the virus from individual to individual in quick succession are
necessary to allow it enough time to mutate into HIV. Furthermore, due to its relatively low
person-to-person transmission rate, it can only spread throughout the population in the
presence of one or more high-risk transmission channels, which are thought to have been
absent in Africa prior to the 20th century.
Specific proposed high-risk transmission channels, allowing the virus to adapt to humans
and spread throughout the society, depend on the proposed timing of the animal-to-human

crossing. Genetic studies of the virus suggest that the most recent common ancestor of the
HIV-1 M group dates back to circa 1910. Proponents of this dating link the HIV epidemic
with the emergence of colonialism and growth of large colonial African cities, leading to
social changes, including different patterns of sexual contact (especially multiple, concurrent
partnerships), the spread of prostitution, and the concomitant high frequency of genital
ulcer diseases (such as syphilis) in nascent colonial cities. While transmission rates of HIV
during vaginal intercourse are typically low, they are increased many fold if one of the
partners suffers from a sexually transmitted infection resulting in genital ulcers. Early 1900s
colonial cities were notable due to their high prevalence of prostitution and genital ulcers to
the degree that as of 1928 as many as 45% of female residents of eastern Leopoldvillewere
thought to have been prostitutes and as of 1933 around 15% of all residents of the same
city were infected by one of the forms of syphilis.
An alternative view — unsupported by evidence — holds that unsafe medical practices in
Africa during years following World War II, such as unsterile reuse of single-use syringes
during mass vaccination, antibiotic, and anti-malaria treatment campaigns, were the initial
vector that allowed the virus to adapt to humans and spread.
The earliest, well-documented case of HIV in a human dates back to 1959 in the Belgian
Congo.The virus may have been present in the United States as early as the mid-to-late
1950s, as a sixteen-year-old male presented with symptoms in 1966 died in 1969.
HIV TROPISM
The term viral tropism refers to the cell types a virus infects. HIV can infect a variety of
immune cells such as CD4+ T cells, macrophages, and microglial cells. HIV-1 entry to
macrophages and CD4+ T cells is mediated through interaction of the virion envelope
glycoproteins (gp120) with the CD4 molecule on the target cells' membrane and also
with chemokine co-receptors.
Macrophage-tropic (M-tropic) strains of HIV-1, or non-syncytia-inducing strains (NSI; now
called R5 viruses) use the β-chemokine receptor CCR5 for entry and are, thus, able to
replicate in both macrophages and CD4+ T cells. This CCR5 co-receptor is used by almost all
primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key
role in several critical aspects of HIV infection. They appear to be the first cells infected by
HIV and perhaps the source of HIV production when CD4+ cells become depleted in the
patient. Macrophages and microglial cells are the cells infected by HIV in the central nervous
system. In tonsils and adenoids of HIV-infected patients, macrophages fuse into
multinucleated giant cells that produce huge amounts of virus.
T-tropic strains of HIV-1, or syncytia-inducing (SI; now called X4 viruses) strains replicate in
primary CD4+ T cells as well as in macrophages and use the α-chemokine receptor, CXCR4,
for entry.
Dual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to
use both CCR5 and CXCR4 as co-receptors for viral entry.
The α-chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1
isolates. It does this by down-regulating the expression of CXCR4 on the surface of HIV
target cells. M-tropic HIV-1 isolates that use only the CCR5 receptor are termed R5; those

that use only CXCR4 are termed X4, and those that use both, X4R5. However, the use of co-
receptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on
macrophages for a productive infection and HIV can also infect a subtype of myeloid
dendritic cells, which probably constitute a reservoir that maintains infection when CD4 + T
cell numbers have declined to extremely low levels.
Some people are resistant to certain strains of HIV. For example, people with the CCR5-
Δ32 mutation are resistant to infection by the R5 virus, as the mutation leaves HIV unable to
bind to this co-receptor, reducing its ability to infect target cells.
Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in
the seminal fluid, which enables the virus to be transmitted from a male to his sexual
partner. The virions can then infect numerous cellular targets and disseminate into the
whole organism. However, a selection process leads to a predominant transmission of the
R5 virus through this pathway. In patients infected with subtype B HIV-1, there is often a co-
receptor switch in late-stage disease and T-tropic variants that can infect a variety of T cells
through CXCR4. These variants then replicate more aggressively with heightened virulence
that causes rapid T cell depletion, immune system collapse, and opportunistic infections
that mark the advent of AIDS. Thus, during the course of infection, viral adaptation to the
use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of
studies with subtype B-infected individuals have determined that between 40 and 50
percent of AIDS patients can harbour viruses of the SI and, it is presumed, the X4
phenotypes.
HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution
to West Africa. The adoption of "accessory genes" by HIV-2 and its more promiscuous
pattern of co-receptor usage (including CD4-independence) may assist the virus in its
adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal
cellular machinery to enable transmission and productive infection has also aided the
establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is
not to kill its host but ultimately become a commensal organism. Having achieved a low
pathogenicity, over time, variants that are more successful at transmission will be selected.
GENETIC VARIABILITY
HIV differs from many viruses in that it has very high genetic variability. This diversity is a
result of its fast replication cycle, with the generation of about 1010 virions every day,
coupled with a high mutation rate of approximately 3 x 10−5 per nucleotide base per cycle of
replication and recombinogenic properties of reverse transcriptase.
This complex scenario leads to the generation of many variants of HIV in a single infected
patient in the course of one day. This variability is compounded when a single cell is
simultaneously infected by two or more different strains of HIV. When simultaneous
infection occurs, the genome of progeny virions may be composed of RNA strands from two
different strains. This hybrid virion then infects a new cell where it undergoes replication. As
this happens, the reverse transcriptase, by jumping back and forth between the two
different RNA templates, will generate a newly synthesized retroviral DNA sequence that is
a recombinant between the two parental genomes. This recombination is most obvious
when it occurs between subtypes.

The closely related simian immunodeficiency virus (SIV) has evolved into many strains,
classified by the natural host species. SIV strains of the African green monkey (SIVagm)
and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their
hosts. These hosts have adapted to the presence of the virus, which is present at high levels
in the host's blood, but evokes only a mild immune response, does not cause the
development of simian AIDS, and does not undergo the extensive mutation and
recombination typical of HIV infection in humans.
In contrast, when these strains infect species that have not adapted to SIV ("heterologous"
or similar hosts such as rhesus or cynomologus macaques), the animals develop AIDS and
the virus generates genetic diversity similar to what is seen in human HIV
infection. Chimpanzee SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with
increased mortality and AIDS-like symptoms in its natural host. SIVcpz appears to have been
transmitted relatively recently to chimpanzee and human populations, so their hosts have
not yet adapted to the virus. This virus has also lost a function of the Nef gene that is
present in most SIVs. For non-pathogenic SIV variants, Nef suppresses T cell activation
through the CD3 marker. Nef's function in non-pathogenic forms of SIV is
to downregulate expression of inflammatory cytokines, MHC-1, and signals that affect T cell
trafficking. In HIV-1 and SIVcpz, Nef does not inhibit T-cell activation and it has lost this
function. Without this function, T cell depletion is more likely, leading to immunodeficiency.
Three groups of HIV-1 have been identified on the basis of differences in the envelope (env)
region: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes
(or clades), based on the whole genome, which are geographically distinct. The most
prevalent are subtypes B (found mainly in North America and Europe), A and D (found
mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in
the phylogenetic tree representing the lineage of the M group of HIV-1. Co-infection with
distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in
which an analysis of global subtype prevalence was made, 47.2% of infections worldwide
were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3%
were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other
subtypes and CRFs. Most HIV-1 research is focused on subtype B; few laboratories focus on
the other subtypes. The existence of a fourth group, "P", has been hypothesised based on a
virus isolated in 2009. The strain is apparently derived from gorilla SIV (SIVgor), first isolated
from western lowland gorillas in 2006.
HIV-2's closest relative is SIVsm, a strain of SIV found in sooty mangabees. Since HIV-1 is
derived from SIVcpz, and HIV-2 from SIVsm, the genetic sequence of HIV-2 is only partially
homologous to HIV-1 and more closely resembles that of SIVsm.
METHODS OF HIV TRANSMISSION

The common methods by which this disease is transmitted includes:
 Having unprotected or condom-less vaginal, oral and anal sex especially with high
risk groups like those who are injection drug abusers or are likely to have HIV
infection.

 Sharing needles for injections with other drug users and patients who are likely to be
HIV positive.
 Sharing sexual toys and objects with an infected person
 Among healthcare workers who can accidentally prick themselves with an infected
needle. The risk is extremely low.
 From an infected mother to her baby before or during birth. Transmission may also
occur via breast milk during lactation. If the mother is treated with anti-HIV
medications, the risk of transmission is low.
 Via transfusion of blood contaminated with HIV. This is very rare these days since
blood is screened for HIV before being transfused.
 Getting a surgical operation with unsterile instruments that may have been used on
HIV positive individuals
 Being exposed to blood, organs or products of an infected person. This is common
among healthcare workers.
 Those who get tattoos or body piercing with shared needles or improperly sterilized
devices.
The virus can enter the blood stream of an individual via cuts and sores in the skin, via the
thin lining on or inside the anus, penis or vagina and via the thin lining of mucus the mouth
and eyes.
HIV infection do not spread by:
 casual touching
 hugging
 light kissing
 contact with unbroken, healthy skin
 being sneezed upon by an infected person
 sharing items of daily use like towels or cutlery and baths, toilets and swimming
pools
 via mosquito or animal bites
 by mouth-to-mouth resuscitation

STAGES OF HIV INFECTION
There are three stages of HIV infection:
1. Acute HIV Infection
Acute HIV infection is the earliest stage of HIV infection, and it generally
develops within 2 to 4 weeks after a person is infected with HIV. During this time,
some people have flu-like symptoms, such as fever, headache, and rash. In the acute
stage of infection, HIV multiplies rapidly and spreads throughout the body. The virus
attacks and destroys the infection-fighting CD4 cells of the immune system. During
the acute HIV infection stage, the level of HIV in the blood is very high, which greatly
increases the risk of HIV transmission.
2. Chronic HIV Infection
The second stage of HIV infection is chronic HIV infection (also called asymptomatic
HIV infection or clinical latency). During this stage of the disease, HIV continues to
multiply in the body but at very low levels. People with chronic HIV infection may not
have any HIV-related symptoms, but they can still spread HIV to others. Without
treatment with HIV medicines, chronic HIV infection usually advances to AIDS in 10
years or longer, though it may take less time for some people.
3. AIDS
AIDS is the final, most severe stage of HIV infection. Because HIV has severely
damaged the immune system, the body can’t fight off opportunistic infections.
(Opportunistic infections are infections and infection-related cancers that occur
more frequently or are more severe in people with weakened immune systems than
in people with healthy immune systems.) People with HIV are diagnosed with AIDS if
they have a CD4 count of less than 200 cells/mm3 or if they have certain
opportunistic infections. Without treatment, people with AIDS typically survive
about 3 years.
SYMPTOMS OF HIV INFECTION
HIV or human immunodeficiency virus infection passes through a series of stages or steps
before it becomes full blown AIDS. These stages of infection are:
1. Seroconversion illness
2. Asymptomatic infection
3. Persistent generalised lymphadenopathy (PGL)
4. Symptomatic infection
5. AIDS

1. Seroconversion illness
This occurs in 1 to 6 weeks after acquiring the infection. There may be symptoms in 20 to
60% patients. Common symptoms are:
 fever with swollen lymph nodes

 weakness
 feeling unwell
 body ache
 headache
 sore throat
 diarrhoea
 rash
 nerve damage or pain
Acute infection may be asymptomatic. The feeling is similar to a bout of flu.
2. Asymptomatic infection
After seroconversion, virus levels are low and replication continues slowly. CD4 and CD8
lymphocyte levels are normal. This stage has no symptoms and may persist for years
together.
3. Persistent generalised lymphadenopathy (PGL)
This stage has typical lymph node swelling of over 1cm in diameter in at least two sites apart
from the groin. The lymph nodes are swollen for three months or longer and not due to any
other cause.
4. Symptomatic infection
This stage manifests with symptoms such as fever, night sweats, diarrhoea, and weight loss.
In addition, there may be infections with organisms that normally cause minor or mild
illnesses. These are called opportunistic infections. This includes fungal infections like oral
candidial infection, vaginal or penile candida infections, oral hairy leukoplakia, seborrhoeic
dermatitis tinea infections and viral infections like herpes zoster, recurrent herpes simplex.
This collection of symptoms and signs is referred to as the AIDS-related complex (ARC) and
is regarded as a prodrome or precursor to AIDS.

5. AIDS
This stage is characterized by severe immunodeficiency. There are signs of life-threatening

infections and unusual tumours. There are symptoms such as:
 persistent tiredness
 night sweats
 weight loss
 persistent diarrhoea
 blurred vision
 white spots on the tongue or mouth (leukoplakia)
 dry cough
 shortness of breath
 fever of above 37C (100F) that lasts a number of weeks
 swollen glands that last for more than three months
Other infections like tuberculosis and pneumonia may occur at this stage. This stage is
characterized by CD4 T-cell count below 200 cells/mm3.
PATHOPHYSIOLOGY OF HIV INFECTION
Fig 2 : The HIV replication cycle

The HIV virion enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its
surface to receptors on the target cell followed by fusion of the viral envelope with the
target cell membrane and the release of the HIV capsid into the cell.
Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike)
on the HIV viral envelope and both CD4 and a chemokine co-receptor (generally
either CCR5 or CXCR4, but others are known to interact) on the target cell surface.Gp120
binds to integrin α4β7 activating LFA-1, the central integrin involved in the establishment
of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.The gp160
spike contains binding domains for both CD4 and chemokine receptors.
The first step in fusion involves the high-affinity attachment of the CD4 binding domains
of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex
undergoes a structural change, exposing the chemokine receptor binding domains of gp120
and allowing them to interact with the target chemokine receptor.This allows for a more
stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to
penetrate the cell membrane. Repeat sequences in gp41, HR1, and HR2 then interact,
causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure
brings the virus and cell membranes close together, allowing fusion of the membranes and
subsequent entry of the viral capsid.
Entry to the cell
Fig 3 : Mechanism of viral entry: 1. Initial interaction between gp120 and CD4. 2. Conformational
change in gp120 allows for secondary interaction with CCR5. 3. The distal tips of gp41 are inserted
into the cellular membrane. 4. gp41 undergoes significant conformational change; folding in half
and forming coiled-coils. This process pulls the viral and cellular membranes together, fusing
them.
After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse
transcriptase, integrase, ribonuclease, and protease, are injected into the cell. During the
microtubule-based transport to the nucleus, the viral single-strand RNA genome is
transcribed into double-strand DNA, which is then integrated into a host chromosome.
HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using
mannose-specific C-type lectin receptors such as DC-SIGN can also be used. DCs are one of
the first cells encountered by the virus during sexual transmission. They are currently
thought to play an important role by transmitting HIV to T-cells when the virus is captured in

the mucosa by DCs. The presence of FEZ-1, which occurs naturally in neurons, is believed to
prevent the infection of cells by HIV.
HIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur
exclusively at the plasma membrane. More recently, however, productive infection by pH-
independent, clathrin-dependent endocytosis of HIV-1 has also been reported and was
recently suggested to constitute the only route of productive entry.
Fig 4 : The HIV replication and maturation process
Replication and transcription

Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates
the positive-sense single-stranded RNA genome from the attached viral proteins and copies
it into a complementary DNA (cDNA) molecule. The process of reverse transcription is
extremely error-prone, and the resulting mutations may cause drug resistance or allow the
virus to evade the body's immune system. The reverse transcriptase also has ribonuclease
activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent
DNA polymerase activity that creates a sense DNA from the antisense cDNA. Together, the
cDNA and its complement form a double-stranded viral DNA that is then transported into
the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out
by another viral enzyme called integrase.
The integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To
actively produce the virus, certain cellular transcription factors need to be present, the most
important of which is NF-κB (nuclear factor kappa B), which is upregulated when T cells

become activated. This means that those cells most likely to be targeted, entered and
subsequently killed by HIV are those currently fighting infection.
During viral replication, the integrated DNA provirus is transcribed into RNA, some of which
then undergo RNA splicing to produce mature mRNAs. These mRNAs are exported from the
nucleus into the cytoplasm, where they are translated into the regulatory
proteins Tat (which encourages new virus production) and Rev. As the newly produced Rev
protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies
of virus RNAs and allows them to leave the nucleus. Some of these full-length RNAs function
as new copies of the virus genome, while others function as mRNAs that are translated to
produce the structural proteins Gag and Env. Gag proteins bind to copies of the virus RNA
genome to package them into new virus particles.
HIV-1 and HIV-2 appear to package their RNA differently. HIV-1 will bind to any appropriate
RNA. HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein
itself.
Recombination
Two RNA genomes are encapsulated in each HIV-1 particle (see Structure and genome of
HIV). Upon infection and replication catalyzed by reverse transcriptase, recombination
between the two genomes can occur. Recombination occurs as the single-strand (+)RNA
genomes are reverse transcribed to form DNA. During reverse transcription, the nascent
DNA can switch multiple times between the two copies of the viral RNA. This form of
recombination is known as copy-choice. Recombination events may occur throughout the
genome. Anywhere from two to 20 recombination events per genome may occur at each
replication cycle, and these events can rapidly shuffle the genetic information that is
transmitted from parental to progeny genomes.
Viral recombination produces genetic variation that likely contributes to the evolution of
resistance to anti-retroviral therapy. Recombination may also contribute, in principle, to
overcoming the immune defenses of the host. Yet, for the adaptive advantages of genetic
variation to be realized, the two viral genomes packaged in individual infecting virus
particles need to have arisen from separate progenitor parental viruses of differing genetic
constitution. It is unknown how often such mixed packaging occurs under natural
conditions.
Bonhoeffer et al. suggested that template switching by reverse transcriptase acts as a repair
process to deal with breaks in the single-stranded RNA genome. In addition, Hu and
Temin suggested that recombination is an adaptation for repair of damage in the RNA
genomes. Strand switching (copy-choice recombination) by reverse transcriptase could
generate an undamaged copy of genomic DNA from two damaged single-stranded RNA
genome copies. This view of the adaptive benefit of recombination in HIV could explain why
each HIV particle contains two complete genomes, rather than one. Furthermore, the view
that recombination is a repair process implies that the benefit of repair can occur at each
replication cycle, and that this benefit can be realized whether or not the two genomes
differ genetically. On the view that recombination in HIV is a repair process, the generation
of recombinational variation would be a consequence, but not the cause of, the evolution of
template switching.

HIV-1 infection causes chronic ongoing inflammation and production of reactive oxygen
species. Thus, the HIV genome may be vulnerable to oxidative damages, including breaks in
the single-stranded RNA. For HIV, as well as for viruses generally, successful infection
depends on overcoming host defensive strategies that often include production of genome-
damaging reactive oxygen. Thus, Michod et al. suggested that recombination by viruses is an
adaptation for repair of genome damages, and that recombinational variation is a byproduct
that may provide a separate benefit.
Assembly and release
Fig 5 : HIV assembling on the surface of an infected macrophage. The HIV virions have been marked with a
green fluorescent tag and then viewed under a fluorescent microscope.
The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma
membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic
reticulum and is transported to the Golgi complex where it is cleaved by furin resulting in
the two HIV envelope glycoproteins, gp41 and gp120.These are transported to the plasma
membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell.
The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the
plasma membrane along with the HIV genomic RNA as the forming virion begins to bud
from the host cell. The budded virion is still immature as the gag polyproteins still need to
be cleaved into the actual matrix, capsid and nucleocapsid proteins. This cleavage is
mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of
the protease inhibitor class. The various structural components then assemble to produce a
mature HIV virion. Only mature virions are then able to infect another cell.
Spread within the body

The classical process of infection of a cell by a virion can be called "cell-free spread" to
distinguish it from a more recently-recognized process called "cell-to-cell spread". In cell-
free spread (see figure), virus particles bud from an infected T cell, enter the blood or

extracellular fluid and then infect another T cell following a chance encounter. HIV can also
disseminate by direct transmission from one cell to another by a process of cell-to-cell
spread, for which two pathways have been described. Firstly, an infected T cell can transmit
virus directly to a target T cell via a virological synapse. Secondly, an antigen-presenting cell
(APC), such as a macrophage or dendritic cell, can transmit HIV to T cells by a process that
either involves productive infection (in the case of macrophages) or capture and transfer of
virions in trans (in the case of dendritic cells). Whichever pathway is used, infection by cell-
to-cell transfer is reported to be much more efficient than cell-free virus spread. A number
of factors contribute to this increased efficiency, including polarised virus budding towards
the site of cell-to-cell contact, close apposition of cells, which minimizes fluid-phase
diffusion of virions, and clustering of HIV entry receptors on the target cell to the contact
zone. Cell-to-cell spread is thought to be particularly important in lymphoid tissues where
CD4+ T cells are densely packed and likely to interact frequently. Intravital imaging studies
have supported the concept of the HIV virological synapse in vivo. The hybrid spreading
mechanisms of HIV contribute to the virus' ongoing replication in spite of anti-retroviral
therapies.
THE BERLIN PATIENT

Gene therapy approaches have recently come to the forefront ofalternative methods in the
quest for the development of curative strategies for the treatment of human
immunodeficiency virus (HIV)-1–infected patients. Nearly all of these studies have been
aimed at developing infection-resistant immune cell populations highlighting the findings ,
in which a single HIV-1–infected patient, known as the “Berlin patient”, was effectively
cured of HIV following allogeneic hematopoietic stem cell transplantation (HSCT) from a
CCR5-null donor.1 While several questions remain concerning what aspects of treatment or
if multiple interventions led to the cure of this patient, a new role for gene therapy in the
pursuit of a cure for HIV/acquired immunodeficiency syndrome has emerged. Timothy
Brown, known as the Berlin patient, was indeed functionally cured of HIV. Viral DNA and
RNA were undetectable in peripheral blood mononuclear cells, lymphoid tissue and in all
other tissues examined, and there is evidence of the eradication of viral reservoirs
demonstrated by the nearly complete absence of immunological responses against
HIV.Based on their findings, the authors concluded that the therapy undergone by Timothy
Brown led to the first clinical cure of an HIV-1–infected patient. There continues to be an
intense debate as to what specific components of Timothy Brown’s treatment led to his
functional cure. Could an intense conditioning regimen that includes total body irradiation,
immune suppression with cyclosporine A, and CD3+ T-cell depletion with antithymocyte
globulin eliminate viral reservoirs? Did graft-versus-host disease effectively lead to the
eradication of all HIV-infected cells? Can the cure be attributed to CCR5−/− HSC transplant
or would a similar outcome be attainable following allogeneic transplantation of wild-type
HSCs? This latter possibility is currently being examined in two patients heterozygous for the
CCR5 delta 32 deletion. after allogeneic transplant from wild-type donors, both patients
maintain undetectable levels of viral DNA or RNA in peripheral blood mononuclear cells.
Although these patients have remained on HAART following transplantation by performing
allogeneic, wild-type HSC transplants on patients with fully suppressed HIV replication, viral
reservoirs may be reduced and/or eliminated with the onset of full donor chimerism.

Allogeneic transplantation may prove effective at reducing viral reservoirs and even
providing cure; however, its associated risks suggest that this approach should only be
considered for HIV-1–infected patients being treated for malignancies.
CURRENT HIV/AIDS TREATMENT

The current state-of-the-art treatment modality for HIV/AIDS is HAART, where three or
more antiretroviral drugs are given to patients simultaneously. The drugs used in
combination are in most cases from different classes that work based on different
mechanisms. Despite the remarkable successes with the current HAART treatment for
HIV/AIDS, there are still various challenges remaining. The major difficulty has been the
failure of the treatment, typically due to poor patient compliance . Due to the need to take
the medication daily for a lifetime, patients fail to adhere to the treatment schedule, leading
to ineffective drug levels in the body and rebound of viral replication.
Moreover, in some patients, the virus develops resistance to particular combinations of
drugs even with good adherence. Drug resistance is mainly caused by the high genetic
diversity of HIV-1 and the continuous mutation it undergoes. This problem is being
addressed with individualized therapy, whereby resistance testing is performed to select a
combination of drugs that is most effective for each patient. In addition, side effects due to
toxicities of the drugs are also a concern. There are reports that patients taking HAART
experience increased rates of heart disease, diabetes, liver disease, cancer and accelerated
aging. Most experts agree that these effects could be due to the HIV infection itself or co-
infection with another virus, such as co-infection with hepatitis C virus resulting in liver
disease. However, the toxicities resulting from the drugs used in HAART could also
contribute to these effects.
Under current treatment, complete eradication of the virus from the body has not been
possible. The major cause for this is that the virus resides in ‘latent reservoirs’ within
memory CD4+ T cells and cells of the macrophage–monocyte lineage .A major study recently
found that, in addition to acting as latent reservoirs, macrophages significantly contribute to
the generation of elusive mutant viral genotypes by serving as the host for viral genetic
recombination .The cells that harbor latent HIV are typically concentrated in specific
anatomic sites, such as secondary lymphoid tissue, testes, liver, kidney, lungs, gut and the
CNS .The eradication of the virus from such reservoirs is critical to the effective long-term
treatment of HIV/AIDS patients. Therefore, there is a great need to explore new approaches
for developing nontoxic, lower-dosage treatment modalities that provide more sustained
dosing coverage and effectively eradicate the virus from the reservoirs, avoiding the need
for lifetime treatments.
ANTIRETROVIRAL THERAPY (ART)

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs in
an attempt to control HIV infection. There are several classes of antiretroviral agents that
act on different stages of the HIV life-cycle. The use of multiple drugs that act on different

viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the
patient's total burden of HIV, maintains function of the immune system, and
prevents opportunistic infections that often lead to death.
The first effective therapy against HIV was the nucleoside reverse transcriptase
inhibitor (NRTI), zidovudine (AZT). It was approved by the US FDA in 1987.
Fig 6: Antiretroviral therapy and drug targets
There are six classes of drugs, which are usually used in combination, to treat HIV infection.
Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that
the drug inhibits. Typical combinations include 2 Nucleoside reverse transcriptase inhibitors
(NRTI) as a "backbone" along with 1 Non-Nucleoside reverse transcriptase inhibitor (NNRTI),
protease inhibitor (PI) or Integrase inhibitors (also known as integrase nuclear strand
transfer inhibitors or INSTIs) as a "base”.
i. Entry inhibitors
Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the
host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two currently
available agents in this class. Maraviroc works by targeting CCR5, a co-receptor located on
human helper T-cells. Caution should be used when administering this drug however due to
a possible shift in tropism which allows HIV to target an alternative co-receptor such
as CXCR4. In rare cases, individuals may have a mutation in the CCR5 delta gene which
results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow
progression of the disease. However, as mentioned previously, this can be overcome if an
HIV variant that targets CXCR4 becomes dominant. To prevent fusion of the virus with the
host membrane, enfuvirtide can be used. Enfuvirtide is a peptide drug that must be injected
and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive
hetero six-helix bundle, therefore preventing infection of host cells.

ii. Nucleoside/nucleotide reverse transcriptase inhibitors

Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transcriptase
inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse
transcription. HIV is an RNA virus and hence unable to become integrated into the DNA in
the nucleus of the human cell; it must be "reverse" transcribed into DNA. Since the
conversion of RNA to DNA is not done in the mammalian cell it is performed by a viral
protein which makes it a selective target for inhibition. NRTIs are chain terminators such
that once incorporated, work by preventing other nucleosides from also being incorporated
into the DNA chain because of the absence of a 3' OH group. Both act as competitive
substrate inhibitors. Examples of currently used NRTIs
include zidovudine, abacavir, lamivudine, emtricitabine, and tenofovir.
iii. Non-nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by
binding to an allosteric site of the enzyme; NNRTIs act as non-competitive
inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by
reverse transcriptase by binding near the active site. NNRTIs can be further classified into
1st generation and 2nd generation NNRTIs. 1st generation NNRTIs
include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine. HIV-
2 is naturally resistant to NNRTIs.
iv. Integrase inhibitors

Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs)
inhibit the viral enzyme integrase, which is responsible for integration of viral DNA into the
DNA of the infected cell. There are several integrase inhibitors currently under clinical trial,
and raltegravir became the first to receive FDA approval in October 2007. Raltegravir has
two metal binding groups that compete for substrate with two Mg2+ ions at the metal
binding site of integrase. As of early 2014, two other clinically approved integrase inhibitors
are elvitegravir and dolutegravir.
v. Protease inhibitors
Protease inhibitors block the viral protease enzyme necessary to produce mature virions
upon budding from the host membrane. Particularly, these drugs prevent the cleavage of
gag and gag/pol precursor proteins. Virus particles produced in the presence of protease
inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors
are lopinavir, indinavir, nelfinavir, amprenavir and ritonavir. Darunavir and atazanavir are
currently recommended as first line therapy choices. Maturation inhibitors have a similar
effect by binding to gag, but development of two experimental drugs in this
class, bevirimat and vivecon, was halted in 2010. Resistance to some protease inhibitors is
high. Second generation drugs have been developed that are effective against otherwise
resistant HIV variants.

vi. Combination therapy

The life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through
replication, assembly, and release of additional viruses, to infection of other cells. HIV
lacks proofreading enzymes to correct errors made when it converts
its RNA into DNA via reverse transcription. Its short life-cycle and high error rate cause the
virus to mutate very rapidly, resulting in a high genetic variability of HIV. Most of
the mutations either are inferior to the parent virus (often lacking the ability to reproduce at
all) or convey no advantage, but some of them have a natural selection superiority to their
parent and can enable them to slip past defenses such as the human immune system and
antiretroviral drugs. The more active copies of the virus, the greater the possibility that one
resistant to antiretroviral drugs will be made.
When antiretroviral drugs are used improperly, multi-drug resistant strains can become the
dominant genotypes very rapidly. In the era before multiple drug classes were available
(pre-1997), the reverse transcriptase
inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially
or in combination leading to the development of multi-drug resistant mutations.
Antiretroviral combination therapy defends against resistance by suppressing HIV
replication as much as possible, thus reducing the potential pool of spontaneous resistance
mutations.
TOWARDS A CURE
People living with HIV can currently expect to live a normal life span if able to achieve
durable viral suppression on combination antiretroviral therapy. However this requires
lifelong medication and will still suffer from higher rates of cardiovascular, renal, liver and
neurologic disease. This has prompted further research towards a cure for HIV. the so-called
"Berlin patient" has been potentially cured and has been off of treatment since 2006 with
no detectable virus.This was achieved through two bone marrow transplants that replaced
his immune system with a donor's that did not have the CCR5 cell surface receptor, which is
needed for some variants of HIV to enter a cell.
APPROACH
Technology have become advanced day by day. We have a wide range of sectors ,tools ,
gadgets that has made our task easy and can help us move towards a more specific goal.
Today the field of bioengineering, biotechnology, pharmacy ,chemistry and many more are
working together to bring more fruitful results. The Berlin patient was cured of AIDS
because bone marrow transplants that replaced his immune system with a donor's that did
not have the CCR5 cell surface receptor, which is needed for some variants of HIV to enter a
cell. The mutant allele of CCR5, CCR5 delta 32 encodes a nonfunctional truncated protein
that is not transported to the cell surface. So, from this review ,the author here wants to
deliver that if we are able to synthesise this mutant gene through artificial gene synthesis
method and incorporate into patient through gene therapy can be a possible approach for
the cure of AIDS.

CONCLUSION
AIDS is a global scourge that has killed millions, has brought heartache and suffering to
millions more, and is likely to continue its grim lethal crescendo for the foreseeable future.
The success of HAART in controlling HIV-1 offers hope, but the difficulties of this therapy
and the ability of HIV-1 to mutate into drug-resistant variants necessitate continuous
development of new therapies. The sobering results of clinical gene therapy trials for AIDS
are cause, not for despair, but for reflection. Gene delivery may yet have a role to play in
the fight against AIDS.
The author would like to conclude by saying that merging biotechnology and bioengineering
methods along with pharmacology may produce an effective cure for AIDS.
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Major Project On Novel Approach For The Cure of Aids

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A REVIEW ON

“NOVEL APPROACH FOR THE CURE OF AIDS”

Chhattisgarh Swami Vivekanand Technical University, Bhilai

In Partial Fulfilment of the requirement for the degree

CHHATTISGARH SWAMI VIVEKANAND TECHNICAL

B.Pharma 8th Sem

RUNGTA COLLEGE OF PHARMACEUTICAL SCIENCE &

Date: Kritika Kanoujia

S.NO. TITLE PAGE NO.

3. AIDS (ACQUIRED IMMUNODEFICIENCY SYNDROME) 8

4. ABOUT HIV 8-9

9. STAGES OF HIV INFECTION 16

10. SYMPTOMS OF HIV INFECTION 16-18

11. PATHOPHYSIOLOGY OF HIV INFECTION 18-23

13. CURRENT HIV/AIDS TREATMENT 24

14. ANTIRETROVIRAL THERAPY (ART) 24-27

15. TOWARDS A CURE 27

18. REFERENCES 28-31

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 6

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 7

AIDS (ACQUIRED IMMUNODEFICIENCY SYNDROME)

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 8

STRUCTURE AND GENOME

Fig 1: Structure of HIV

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 9

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 10

Left to right: the African green

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 11

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 12

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 13

METHODS OF HIV TRANSMISSION

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 14

HIV infection do not spread by:

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 15

STAGES OF HIV INFECTION

There are three stages of HIV infection:

1. Acute HIV Infection

2. Chronic HIV Infection

SYMPTOMS OF HIV INFECTION

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 16

 fever with swollen lymph nodes

Acute infection may be asymptomatic. The feeling is similar to a bout of flu.

3. Persistent generalised lymphadenopathy (PGL)

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 17

This stage is characterized by severe immunodeficiency. There are signs of life-threatening

PATHOPHYSIOLOGY OF HIV INFECTION

Fig 2 : The HIV replication cycle

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 18

Entry to the cell

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 19

Fig 4 : The HIV replication and maturation process

Replication and transcription

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 20

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 21

Assembly and release

Spread within the body

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 22

THE BERLIN PATIENT

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 23

CURRENT HIV/AIDS TREATMENT

ANTIRETROVIRAL THERAPY (ART)

Rungta College of Pharmaceutical Science and Research (2017-2018) Page 24

Fig 6: Antiretroviral therapy and drug targets