HIV-1 replicates, evolves in HIV-1 controllers

Mens H. J Virol. 2010;84:12971-12981.

Issue: January 2011

Most HIV-1 controllers are infected with a strain of HIV-1 that continues to replicate and evolve. Rather than hosting a poorly replicating strain of HIV-1, HIV-1 controllers are suppressing the virus, according to a study published in the Journal of Virology.

Helene Mens, MD, of the National Cancer Institute and NIH, and colleagues aimed to determine whether HIV-1 evolves via cycles of replication or whether replication is absent or blocked among HIV-1 controllers. To do this, they isolated HIV-1 RNA from large volumes of plasma and amplified single genome sequences of both pro-rt and env longitudinally. The genes were sequenced with plasma samples from 21 HIV-1 controllers infected for a median of 11 years, with low-level viremia at a median of 0.3 copies/mL to 0.8 copies/mL. Less than half of the cohort carried known protective human leukocyte antigen (HLA) types (B*57/27).

Results of the study revealed that HIV-1 controllers had lower viremia (<20 copies/mL vs. 264,980 copies/mL; P<.0001) and higher peripheral CD4+ T-cell counts (744 cells/mcL vs. 402 cells/mcL; P<.0003) than non-controllers. Although the level of viremia was lower in HIV-1 controllers, the researchers found that pro-rt and env evolved at rates that were not greatly different.

The modes of selection were similar regardless of control status, the researchers reported, and in both groups, pro-rt evolved under purifying selection, whereas env evolved under positive selection.

“Viral diversity and adaptive events associated with immune escape were found to be restricted in HIV-1 controllers, suggesting that replication occurs in the face of less overall immune selection,” the researchers wrote.

According to the researchers, this is the first documentation of HIV-1 pro-rt and env evolving in this patient group at rates somewhat lower than in HIV-1 non-controllers and in HLA B*57/27-positive and HLA B*57/27-negative patients.

“These results imply that natural control is driven by host immune responses rather than infection with a replication incompetent virus (a defect virus). Based on the analyses of selection in viral genes, we could also draw the conclusion that the virus is replicating against a strong cellular immune pressure and not a humeral immune pressure, suggesting that cellular immune responses are more likely to mediate control than humeral (antibody) responses,” Mens told Infectious Disease News.

Mens said testing of HIV-1 RNA and CD4+ T cells in HIV-1 controllers should continue. “It is important to find out if viral replication is driving immune activation and inflammation in HIV-1 controllers and if they, therefore, may benefit from antiretroviral therapy,” she said.

“Results suggest that HIV-1 is undergoing full cycles of replication in at least 40% of the HIV-1 controllers in the cohort. Evolution of plasma viruses in HIV-1 controllers was found in HLA B*57/27-positive, as well as HLA B*57/27-negative, individuals, suggesting that virus replication was not dependent on the absence of protective HLA alleles,” the researchers wrote.

“This study contributes greatly to how we understand the mechanisms of natural control of HIV-1,” Mens concluded. “By showing that the virus is replicating in HIV-1 controllers, we also indirectly demonstrate that host immune mechanisms are responsible for viral control and that progression to AIDS can be delayed, even though viral replication is not completely stopped. The results raise hope that an effective vaccine that can delay disease progression and prevent transmission can be developed.”

Disclosures: Dr. Mens has no relevant financial disclosures.

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