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HIV Genetic Diversity Does Not Change Much After Complete Viral Control
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
HIV diversity and population structure in plasma changed hardly at all after 10 antiretroviral-treated people got their viral load to undetectable levels, a result confirmed in monkeys [1]. The investigators believe their findings suggest antiretroviral therapy completely blocks active cycles of HIV replication .
Mary Kearney (National Cancer Institute [NCI], Frederick, Maryland) analyzed 1143 HIV-1 gag, pro, and pol sequences obtained by single-genome sequencing immediately before antiretroviral began and over the course of treatment in 10 people who reached and maintained a viral load below 75 copies. Study participants had been infected for 1 to 10 years, and their treatment lasted from a half month to 5 years. Kearney and colleagues calculated genetic diversity by determining average pairwise difference in aligned sequences from samples collected before and during treatment. They also used phylogenetic analysis to look for genetic variation over time.
Average pairwise difference in individual patients ranged from 0.2% to 2.5% before antiretroviral therapy. Treatment pushed viral loads below 75 copies/mL in all patients Neither average pairwise difference calculations nor phylogenetic analysis disclosed any change in genetic diversity or viral population structure after viral control with therapy, even though viral load fell 10,000-fold in some study participants after 1 year of treatment. Kearney detected no resistance-related mutations in any patient before or during treatment.
The NCI team also analyzed plasma samples from 6 monkeys infected with RT-SHIV, a pathogenic simian immunodeficiency virus with an HIV coat. The macaques had been infected for a year, and antiretroviral treatment lasted 1 month. Treatment failed in one animal. As in the 10 antiretroviral-treated people, average pairwise difference disclosed no change in sequence diversity or viral population structure before and during antiretroviral therapy in successfully treated monkeys.
Earlier work by Robert Siliciano's Johns Hopkins group found that, despite wide diversity of HIV-1 pol sequences in resting CD4 cells of people with treatment-induced viral loads below 50 copies, residual virus in plasma became dominated by a homogeneous population with identical pol sequences [2]. Patients released these so-called predominant plasma clones into the circulation for months to years with no evident pol sequence changes. Kearney and coworkers identified the same type of predominant plasma clone in one of their patients who took successful antiretroviral therapy for 4 years. But overall viral diversity persisted in this person.
The NCI investigators believe the relentlessly diverse viral populations in these patients "suggest that both short- and long-lived cells are infected with similar virus populations before therapy is initiated [and] that active cycles of HIV-1 replication are completely blocked by antiretroviral therapy." Viral diversity in their one 4-year-treated patient and in Siliciano's study suggest, though, that "infected cell populations are slowly lost during antiretroviral therapy," and predominant plasma clones emerge as a result.
References
1. Kearney M, Yu S, Shao W, Mellors JW, Coffin JM, Maldarelli F. HIV-1 plasma virus diversity persists despite suppression with antiretroviral therapy. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 6.
2. Bailey JR, Sedaghat AR, Kieffer T, et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J Virol. 2006;80:6441-6457.
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