Human Immunodeficiency Virus

BY:

MANISH DHAWAN

INTRODUCTION Family: Retroviridae Genus: Lentiviridae Disease that HIV causes, AIDS was first

reported in the U.S. in 1981 in L.A. and New York

Causative agent discovered and characterized by Luc Montagnier of France and Robert Gallo of the US in 1983-84.

Retrovirus having:

Reverse transcriptase

Antigenic strains : HIV-1 and HIV-2 HIV-1(virulent strain) is most prominent in

U.S., Canada and Europe HIV-2 (less virulent) common in certain

parts of West Africa, it is closely related to simian immunodeficiency virus (SIV) found in monkey

HIV-1 differs significantly from HIV-2/SIV.

structure Each virion expresses 72 glycoprotein projections composed of gp120 and gp41

The viral envelope derives from the host cell and contains some host-cell membrane proteins, including class I and class II MHC molecules

Within the envelope is the viral core, or nucleocapsid, which includes a layer of a protein called p17 and an inner layer of a protein called p24.

Genome consists of two copies of single-stranded RNA, which are associated with two molecules of reverse transcriptase (p64) and nucleoid proteins p10, a protease,

and p32, an integrase.

Electron micrograph of HIV virions magnified 200,000 times. The glycoprotein projections are faintly visible as “knobs” extending from the periphery of each virion.

Genome of HIV-1 Structural genes

gag :- Group specific antigen, pol :- Reverse transcriptase, Protease

and Integrase, env :- Envelope glycoprotein (gp).

Genes essential for viral replication:

tat :- activates transcription,

rev :- export of unspliced and singly spliced mRNAs from nucleus,

LTR sequence:- promoter and enhancer elements

Genes not essential for viral replication:-

vif :- promotes maturation and infectivity

nef (negative factor) :- Down-regulates Host-cell class I MHC and CD4

vpr , vpx and vpu

StabilityInactivation By :-

Heat a) Autoclave b) hot air oven Glutaraldehyde 2% Hypochlorite 10,000 ppm : 1 in 10 dilution of domestic

bleach Other disinfectants, including alcohols .

Survival of HIV :-

Virus may survive for up to 15 days at room temperature. At 37º C virus can survive for 10-15 days. Over 60º C virus is inactivated 100-fold each hour.

Viral Infection

M-tropic, binds to CD4 and CCR5 of macrophage

T-tropic viruses infect T cells by binding with CD4 and CXCR4.

Viral Replication

HIV infecting a T-lymphocyte

Destruction of T-cells

Pathogenesis :- Latency Period

Destruction of Immune System

HIV-Time Course

Acquired Immunodeficiency Syndrome

• Disease limits the body’s ability to fight infection due to markedly reduced helper T cells

• CD4 count drops below 200 person is considered to have advanced HIV disease

• If preventative medications not started the HIV infected person is now at risk for:– Pneumocystis carinii pneumonia (PCP)– cryptococcal meningitis– toxoplasmosis

NATURAL COURSE OF HIV/AIDS

Stage 1 - Primary

Short, flu-like illness - occurs one to six weeks after infection

Mild symptoms Infected person can

infect other people

Stage 2 - Asymptomatic Lasts for an average of ten years This stage is free from symptoms There may be swollen glands The level of HIV in the blood drops to low levels HIV antibodies are detectable in the blood

Stage 3 - Symptomatic

The immune system deteriorates Opportunistic infections and cancers start to

appear.

Stage 4 - HIV AIDS

The immune system weakens too much as CD4 cells decrease in number.

Opportunistic Infections associated with AIDS

CD4<500 Bacterial infections Tuberculosis (TB) Herpes Simplex Herpes Zoster Vaginal candidiasis Hairy leukoplakia Kaposi’s sarcoma

HIV infection to -> AIDS

Diseases are predictive of the progression to AIDS:

Oral Candidiasis Oral Hairy Leukoplakia

Kaposi’s sarcoma

Epidemiology Worldwide distribution

ESCALATING EPIDEMIC !!!

Source: WHO/UNAIDS/UN The Millennium Development Goals Report, 2009, p.32 and WHO.

Status in India

Blood Detection TestsHIV enzyme-linked immunosorbent assay (ELISA)

Screening test for HIVSensitivity > 99.9%

Western blot Confirmatory testSpeicificity > 99.9% (when combined with ELISA)

HIV rapid antibody test Screening test for HIVSimple to perform

Absolute CD4 lymphocyte count

Predictor of HIV progressionRisk of opportunistic infections and AIDS when <200

HIV viral load tests Best test for diagnosis of acute HIV infectionCorrelates with disease progression and response to HAART

Urine Testing

Urine Western Blot As sensitive as testing

blood Safe way to screen for HIV Can cause false positives in

certain people at high risk for HIV

Oral Testing

Orasure The only FDA approved

HIV antibody. As accurate as blood

testing Draws blood-derived

fluids from the gum tissue.

NOT A SALIVA TEST!

Treatment Options

HAART = Highly Active Anti-Retroviral Treatment

Antiretroviral Drugs (HAART)

Nucleoside Reverse Transcriptase inhibitorsAZT (Zidovudine), Lamivudine

Non-Nucleoside Transcriptase inhibitorsViramune (Nevirapine)

Protease inhibitorsNorvir (Ritonavir), Indinavir (Crixivan)

HEALTH CARE FOLLOW UP OF HIV INFECTED PATIENTSFor all HIV-infected individuals:     CD4 counts every 3–6 months    Viral load tests every 3–6 months and 1 month

following a change in therapy       Toxoplasma IgG serology    CMV IgG serology    Pneumococcal vaccine    Influenza vaccine in season    Hepatitis B vaccine for those who are HBsAb-

negative    Haemophilus influenzae type b vaccination     Papanicolaou smears every 6 months for women

A Vaccine May Be the Only Way to Stop the HIV/AIDS Epidemic

Why AIDS does not fit the paradigm for classic vaccine development• Classic vaccines mimic natural immunity against reinfection generally seen

in individuals recovered from infection; there are no recovered AIDS patients.

• Most vaccines protect against disease, not against infection; HIV infection may remain latent for long periods before causing AIDS.

• Most vaccines protect for years against viruses that change very little over time; HIV-1 mutates at a rapid rate and efficiently selects mutant forms that evade immunity.

• Most effective vaccines are whole-killed or live-attenuated organisms; killed HIV-1 does not retain antigenicity and the use of a live retrovirus vaccine raises safety issues.

• Most vaccines protect against infections that are infrequently encountered; HIV may be encountered daily by individuals at high risk.

• Most vaccines protect against infections through mucosal surfaces of the respiratory or gastrointestinal tract; the great majority of HIV infection is through the genital tract.

• Most vaccines are tested for safety and efficacy in an animal model before trials with human volunteers; there is no suitable animal model for HIV/AIDS at present.

Vaccine strategies under study

Vaccine

constituentsStatus Advantages Disadvantages

Viral surface proteins, gp120

In phase I and II trials, which examine safety

Safe and simple to prepare

Vaccine –elicited antibodies have failed to recognize HIV from patients

Live vector viruses

In phase II trials Markers can control amount and kinds of viral proteins produced

Complicated to prepare

Combinations of elements, such as pure gp120 protein plus canarypox vector

In phase II trials Should stimulate both arms of the immune response at once

Complicated to prepare