NEW YORK (GenomeWeb News) – New research suggests that HIV strains that mutated to evade the immune systems of some hosts — those with advantageous gene variants — are less potent when passed on to others.
South African researchers did genetic analyses of HIV strains isolated from newly infected individuals in Durban, South Africa. They found that certain HIV mutations — apparently acquired to evade the immune systems of previous hosts — were associated with decreased viral load and possibly delayed disease progression. The research appears online today in the journal PLoS Pathogens.
“While the role of host genetics is well established, this study shows that genetic polymorphisms in the transmitted virus can offer survival advantage to a newly infected person,” senior author Carolyn Williamson, a virologist at the University of Cape Town, said in a statement.
An infected individual’s response to HIV depends largely on their immune system. The class I human leukocyte antigen locus influences which HIV antigens or parts of the virus the rest of the immune system recognizes. Another group of immune cells, called cytotoxic T lymphocytes, target specific HIV peptides based on these antigens.
HIV can mutate to evade the immune system. But some HLA gene variants make it impossible for HIV to escape immunity without evolving into a milder form. For instance, HLA-B*57 and HLA-B*5801 code for human leukocyte antigens targeting functionally important parts of the Gag gene, which codes important HIV structural proteins. So even if HIV mutates to escape the immune system — which it often does — it makes itself less fit in the process, reducing HIV replication and delaying AIDS onset.
Consequently, the authors note, HLA variations affect both an individual’s HIV response and their rate of disease progression, making the HLA genotype “[o]ne of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals.”
Previous research suggests that the virus often reverts to its original form when it infects those who lack the “good” HLA gene variants. But it was unclear how new infections with HIV “escape” variants compared with other infections.
To address this, Williamson and her colleagues followed the acute and long-term effects of HIV infection in 21 women who were negative for HLA-B*57, HLA-B*5801, and another variant associated with slow HIV progression, HLA-B*27. The subjects, who were enrolled within a broader study looking at acute and early HIV-1 infections, were initially HIV-negative but considered at high risk for infection. They were monitored monthly and enrolled within three months after infection.
To determine HIV progression, the researchers analyzed the CD4+ T cell counts and viral loads in blood samples that were collected periodically. They also sequenced the HIV Gag region from each infected individual at initial infection as well as three and six months later using reverse transcription followed by an ABI PRISM dye terminator cycle-sequencing kit.
When they compared these Gag sequences, the researchers found two Gag polymorphisms that were associated with higher immune CD4+ cell counts and lower viral loads in nine women. None of the subjects infected with these strains seemed to carry HLA variants that might explain these lower viral levels.
Based on the position of these mutations, the researchers suspected that the women who carried a virus with one or both of the polymorphisms had contracted HIV from someone who had a beneficial, HLA-B*57 or HLA-B*5801, variant. Other mutations within the viruses were also consistent with this notion.
As expected, HIV’s “escape” mutations didn’t always stick around when the virus was free from immune pressures elicited by HLA-B*57 or HLA-B*5801 positive hosts. One of the key Gag mutations reverted after six months to two years in 83 percent of the subjects. The other reverted less frequently — only 22 percent of the time — after roughly one and a half to two years of infection. On the other hand, other mutations seemed to stick around or only partly revert.
Interestingly, even when HIV reversion did occur, it did not lead to an immediate increase in viral load in the host. The authors speculated that this could be because the virus’ form at initial infection dictates its infection profile or because of other HLA-related genomic changes that had not reverted. Either way, they say, more research is required to understand this immune selection and its potential application to HIV vaccines.