Dr Richard Hunt

VIDEO LECTURE

VIROLOGY - CHAPTER   SEVEN    PART ELEVEN

HUMAN IMMUNODEFICIENCY VIRUS AND AIDS  

POPULATION POLYMORPHISM

LINKS  TO OTHER HIV AND AIDS SECTIONS ARE AT THE BOTTOM OF THIS PAGE

   Histopathology showing microglial nodule in brain of patient who died of AIDS. Brain microglial nodules are nonspecific microscopic brain lesions often associated with fatal HIV infection. (CDC/Dr. Edwin P. Ewing, Jr.  epe1@cdc.gov)

Figure 29

OTHER CELLS THAT ARE INFECTED BY HIV

Although CD4⁺ T4 cells are usually considered to be the most important cells in the course of AIDS and it is their loss that leads to immune suppression, other cells do become infected. Macrophages are very important as they form a reservoir outside the blood and carry the virus into extravascular tissues. Non-proliferating mature macrophages can support HIV production for a long time without being killed. There is no latency in these cells, the virus just buds. Cytokine production by the infected macrophages is also aberrant leading to a variety of secondary effects. The slim disease that is characteristic of HIV infections in Africa may result from macrophage cytokine disruption. This wasting is very reminiscent of Visna in sheep and Visna infections involve the macrophages. Macrophages and macrophage-like cells are infected via CD4 antigen. Also, since the virus induces good antibodies in the host, cells that express Fc or complement receptors will take up the virus.

Some CD4-negative cells become infected; for example, epithelial cells of the vagina and rectum, endothelial cells of brain capillaries and other cells of the CNS such as astrocytes and glial cells (figure 29). These may take up HIV via a galactocerebroside receptor. Dendritic cells may also be very important. These cells appear to trap virions and carry them to the lymph nodes (see also section 7).

POPULATION POLYMORPHISM AND HIV VARIANTS

Population polymorphism results from the high error rates of reverse transcriptase and RNA polymerase II which are used to replicate the viral genome. The error rate is 1 in 2000 - 10,000 nucleotides. This, together with the high rate of CD4⁺ cell production and infection, means that every possible single point mutation in the viral genome arises daily and almost 1% of all possible double mutations occur each day. As a result, the virus isolated from an AIDS patient is very different from the original infecting virus. Distinct sub-strains differ in cell tropism. Some form syncytia, some do not. As has been already noted, the non-syncytium-inducing macrophage-tropic type is probably the infectious form (Note: most vaccines have been made against the syncytium-inducing form of HIV-1 and polymorphism poses a great obstacle to the successful development of a vaccine). The major variable protein is Gp120 and, within a single patient, HIV-1 commonly varies by 1-6% in the ENV gene. There are some conserved sites in Gp120 in which mutations are presumably  non-viable (e.g. the CD4 binding site). But very often glycosylation masks these conserved sites (which also poses a problem for vaccine development). Gp41 is not as glycosylated and the fusion site needs to be conserved (this may be a possible vaccine site).

Compared to variation within an individual, there is a lot greater variability around the world. HIV-1 genetic subtypes differ by up to 30% in the amino acid sequence of the ENV gene. There are at least 10 subtypes of HIV-1.

Not only is the reverse transcriptase mutation rate a problem. It is possible for a person to be infected by different HIV-1 subtypes resulting in cells becoming co-infected. Resultant viruses have one RNA from one subtype and one from the other. On later rounds of infection recombination occurs. It has been found that a recombinant subtype (HIV-1E) is spreading globally. The impact of these evolving subtypes is great since they may affect the efficacy of tests for infected blood. Moreover, they have to be taken into account when thinking of a vaccine. There is also the possibility that there may be significant differences in the transmissibility of different subtypes (HIV-1 is much more transmissible than HIV-2).
 

STRATEGIES TO COMBAT VIRUS

Chemotherapy: Most anti-HIV drugs are toxic. In addition, present anti-HIV chemotherapy does not stop infection and is unlikely to cure the infected host (see chemotherapy chapter). The most we can hope for is suppression of virion production making AIDS a more tractable disease. Recently great strides towards this goal have made (see appendix 3).

Education: HIV is (fortunately) not highly infectious. It can be avoided by taking the correct precautions. This approach has been very successful in certain countries in containing the spread of AIDS.

Vaccine: This is the best way to protect against  infection. But HIV is a retrovirus and this poses enormous problems for vaccine development (see appendix 1).

PART I HUMAN IMMUNODEFICIENCY VIRUS AND AIDS

PART II HIV AND AIDS, THE DISEASE

PART III COURSE OF THE DISEASE

PART IV PROGRESSION AND COFACTORS

PART V STATISTICS

PART VI  SUBTYPES AND CO-RECEPTORS

PART VII  COMPONENTS AND LIFE CYCLE OF HIV

PART VIII  LATENCY OF HIV

PART IX GENOME OF HIV

PART X  LOSS OF CD4 CELLS

PART XI  OTHER CELLS INFECTED BY HIV AND POPULATION POLYMORPHISM

APPENDIX I  ANTI_HIV VACCINES

APPENDIX II  DOES HIV CAUSE AIDS?

APPENDIX III  ANTI_HIV CHEMOTHERAPY

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