INFECTIOUS DISEASE

TURKISH

VIROLOGY - CHAPTER   SEVEN    

PART ELEVEN

HUMAN IMMUNODEFICIENCY VIRUS AND AIDS 

POPULATION POLYMORPHISM

STRATEGIES TO COMBAT THE VIRUS

CAN HIV BE CURED? 

 

Dr Richard Hunt
Professor
Department of Pathology, Microbiology and Immunology
University of South Carolina School of Medicine

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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).

CAN AN HIV-INFECTED PATIENT BE CURED?

The ultimate aim of research into HIV and AIDS is either prevention using a vaccine or a cure using chemotherapy or some other means. The patient does not need to be completely free of virus and in a “functional” cure, the patient’s immune system keeps any remaining virus under control. This in contrast to a “sterilizing” cure in which virus is completely eliminated from the patient.

There have been a few instances in which a patient known (or highly suspected) to be HIV-positive has been functionally cured. These are, however, exceptional circumstances.

Infant Infection

In 2013, the apparent cure of a neonate born in Mississippi, USA was reported. Few children nowadays acquire HIV from an infected mother because of anti-retroviral treatment of both the mother and baby around the time of birth. However, in July 2010 an expectant mother came to a hospital in rural Mississippi in premature labor. Only then did her doctors and the mother learn that she was HIV-positive. Two PCR blood tests on the two day old infant showed the presence of HIV DNA and HIV RNA, indicating that the infant was also infected. The infant was treated aggressively within two days with AZT, lamivudine and nevirapine. The baby was tested over a period of three weeks for HIV and the presence of virus was confirmed. Chemotherapy was carried on for 18 months and then ceased. At 21 months, the baby was found to be free of HIV. This was done by adding the child’s blood to uninfected CD4+ cells and looking for the production of new HIV. None was found. Only very small amounts of HIV were found in the blood and this was not integrated into cellular DNA (which is necessary for replication).

The treatment of this child was in contrast to the normal drug regimen used in which only one drug is used as a preventative measure. This can reduce infection at birth to 1% whereas without treatment 30% of babies of HIV-positive mothers would be infected.

It was thought that the aggressive treatment early in life stopped the establishment of HIV in memory T cells. However, unfortunately, HIV has reemerged in this patient.

Adult Infection

In 2013, the apparent functional cure of fourteen French patients was reported. They were treated within two months of infection (that is during the primary infection) and now have little detectable HIV after cessation of treatment for four to nine years. It appears that the virus that they do have (in eleven patients under 40 and in three, under 5 copies per ml blood) is controlled by the patients’ immune systems (hence the term functional cure rather than sterilizing cure).

The Berlin Patient

Timothy Ray Brown is the only person whose memory T cells had been infected with HIV known to be cured of HIV infection. But his treatment was extraordinary. He is known as the "Berlin patient." Mr Brown suffered from both leukemia and HIV infection and was "cured" when he received a bone marrow stem cell transplant for his leukemia. This was not related to his HIV infection. The stem cells he received came from a person with HIV-resistant cells. Mr Brown was heterozygous for CCR5-Δ32 which resulted in reduced infectivity by HIV and the donor had a homozygous CCR5-Δ32 mutation in both genomic copies of a gene encoding the cell-surface chemokine receptor CCR5. As a result of the bone marrow transplant, Mr Brown’s circulating CD4+ T-cells were homozygous for CCR5-Δ32, making him HIV-resistant. His virus never reappeared and he was able to cease his antiretroviral medication.

Other cures using bone marrow transplantation

In 2013, it was reported that two HIV-positive men who had been infected for about 30 years had apparently been freed of HIV and were able to be removed from their anti-HIV drug regimen. They had both developed lymphoma and required a bone-marrow transplant, after which there was no detectable HIV in their blood for two years. It is too early to say they have been cured as the provirus may still be present in a quiescent form. It is thought that the transplanted bone marrow may have been protected from HIV by the anti-retroviral drugs and the transplanted cells may have attacked the infected bone marrow

 

OTHER SECTIONS ON HIV

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   POPULATION POLYMORPHISM

APPENDIX I  ANTI-HIV VACCINES

APPENDIX II  DOES HIV CAUSE AIDS?

APPENDIX III  ANTI-HIV CHEMOTHERAPY

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