HIV VIRUS
           LIFE CYCLE
           RNA GENOME
           REGULATION OF HIV GENE EXPRESSION
           RELATION TO OTHER RETROVIRUSES
           TRANSMISSION OF HIV AND AIDS IN HUMANS

HIV INFECTION TARGETS IN HUMANS

POTENTIAL AIDS THERAPIES

A VACCINE FOR AIDS?

Reading Assignment: Lecture notes and illustrations are sufficient. The following readings are supplemental and not required:

1) THE SCIENCE OF AIDS [W.H. Freeman, 1989] (reprint of Scientific American, Oct., 1988)

In particular,

a. The Molecular Biology of the AIDS Virus (Chapter 2).

b. AIDS Therapies (Chapter 8).

KEY CONCEPTS:

• AIDS results from infection with the human retrovirus called HIV (human immunodeficiency virus). The HIV virion infects T4 helper lymphocytes by recognizing a specific glycoprotein in its cell membrane. The cell membrane-like envelope of the virus fuses with that of the T4 cell. The viral genome (RNA) is released into the cell and a DNA copy is made by reverse transcriptase (also released into the cell along with the genomic RNA). The cDNA is integrated into the host chromosome, where it may remain latent (unexpressed) for years. A person infected with HIV is infected for life! The virus remains silent until the host's immune system is stimulated, causing the virus genes to be transcribed, new virus particles to bud from the T4 cells, and infection of more T4 cells. In addition, HIV induces special killer T-cells to destroy uninfected T4 cells as well. Thus the entire immune system's functions are gradually - but irreparably - impaired. The infected individual at this point becomes susceptible to serious disease from secondary infections by any and all other viruses or bacteria. This is the condition known as AIDS (Acquired Immune Deficiency Syndrome).

AIDS (Acquired Immune Deficiency Syndrome)

• No known cure
• Everyone at risk by the three major routes of HIV infection.

 
Transmission of HIV (and AIDS):  exchange of body fluids (Fig HIV-4)
        1)  Unprotected sex
        2)  Blood
                        -blood or blood-product transfusions
                        -sharing of needles by intravenous drug users
        3)  mother to new-born before, during, or soon after birth

• The virion has a cell membrane-like envelope with outwardly protruding knobs consisting of a glycoprotein (gp120) which is anchored to another glycoprotein (gp41) that spans the virus envelope. The trouble-maker for infection is gp120 which binds to T4 helper lymphocytes as the first step of cell invasion by the virus.
• Inside the envelope is a core particle consisting of two proteins, two copies of the virus genome, and two molecules of reverse transcriptase.

 

 
• HIV LIFE CYCLE:
 
After T4 cell is infected with HIV, the genome (after being copied into a DS-DNA) is integrated into a T4 cell's chromosome as a provirus (remember bacteriophage lambda as a prophage?). The virus may remain latent (no viral genes expressed) or it may be transcribed by the host cell's RNA polymerase into mRNAs and genomic RNA. Viral protein synthesis and assembly of new virions then occurs at the cell membrane, some of which becomes part of the new virion's envelope as the virus buds from the cell surface.

• HIV GENOME:

 

 
 
 
 
 

The genome consists of 9,749 nucleotides containing genes for virus proteins (gag, pol, env genes), regulatory proteins (tat, rev, nef genes) infectivity factor (vif gene) and sequences of unknown function. Some of these genes are overlapping and some have coding sequences which are alternatively spliced. There are also LTR (long term repeat) sequences at each end of the genome which are involved in expression of other viral genes and in reverse transcription.
 

• REGULATION OF HIV GENE EXPRESSION:

 

 
 
 
 
 

HIV gene expression is under the control of tat (activates all HIV genes), nef (represses all HIV genes), and rev (represses itself,tat and nef, but turns on all other HIV genes).
 

• RELATION TO OTHER RETROVIRUSES:

 

 
 
 
 
 

Antibody cross-reactivities show that HIV is closely related to a West African monkey retrovirus (SIV, which causes an AIDS-like disease in monkeys) and to a newly discovered human retrovirus (HIV-2) which is found in man in West Africa and may have been transmitted from monkeys to man. HIV-2 may or may not cause AIDS in man.
 

• HIV INFECTION: RECOGNITION BY TARGET CELLS IN HUMANS

 
• IMMUNE CELL [Figure HIV-12] (T4) DESTRUCTION BY HIV

• STRATEGIES FOR ANTI-HIV DRUG THERAPY:

 

 
 
 
 
 

There are at least 7 stages of the HIV life cycle for which disruptive therapies can be envisioned

• AZT - EXAMPLE of One REVERSE TRANSCRIPTASE INHIBITOR WHICH WORKS
• TRIPLE CHEMOTHERPY WHICH SEEMS TO WORK:

 

 
 
 
 
 

2 reverse transcriptase inhibitors and a protease inhibitor in combination
 

• A VACCINE FOR AIDS?

 

 
 
 
 
 

This is a very tough problem, since the virus surface gp120 undergoes constant mutation and change in antigenic determinants, even within an infected individual. But, the effort is great, involving concerted efforts of many scientists in research laboratories and in the biomedical industry. Specific regions of the gp120 molecule have been identified as targets against which to develop antibody-based vaccines. At least two (Salk [whole inactivated virus] and antibodies to gp160) are now undergoing clinical trials in humans.

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        1)  Retrovirus
        2)  (+) Strand virus  (cDNA integrated in genome)
        3)  membrane virus
        4)  polyproteins (cf. poliovirus)
        5)  high mutability (cf. influenza virus)
        6)  overlapping genes
        7)  alternate splicing
        8)  complex regulation of gene expression