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Ongoing HIV Infection of CD4s May Explain Poor CD4 Gains With Sub-50 Load
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52nd ICAAC, September 9-12, 2012, San Francisco
Mark Mascolini
HIV DNA in CD4-cell cytoplasm--a marker of recent CD4-cell infection--could be detected in one third of antiretroviral-treated patients with an undetectable viral load and correlated with poor CD4-cell gains and greater CD8-cell activation in a small study in Montpellier and Nimes, France [1]. The researchers believe the linear HIV DNA assay they designed may have several uses and could offer a convenient tool to assess the power of antiretroviral therapy (ART).
Poor CD4 response in a subset of people who respond virologically to ART is a long-appreciated phenomenon. But the reasons for this disconnect remain difficult to pin down. Researchers in Montpellier and Nimes hypothesized that ongoing infection of CD4 cells despite viral suppression could be one explanation. Specifically, they proposed, "persistent production of HIV reverse transcripts in recently infected cells" could be a cause.
To test their hypothesis, the researcher tried to find a link between ongoing viral replication, immune activation, and poor CD4 gains in antiretroviral-treated people with an undetectable viral load. As a marker of persistent infection, they picked detection of HIV DNA in cytoplasm of circulating CD4 cells. Because this viral product has a short half-life, they theorized that it offers a reliable marker of recent CD4-cell infection.
The investigators recruited 35 virologic responders from the university hospitals in Montpellier and Nimes. They used quantitative PCR to detect HIV DNA in CD4-cell cytoplasm. To exclude the possibility of contamination of the cytoplasm by nuclear extract, they determined whether the ratio of DNA copies in cytoplasm versus nucleus was significantly higher for HIV DNA than for CCR5 DNA.
Twenty-five of 35 study participants were men, and their age averaged 48 (range 30 to 70). Duration of HIV infection averaged 7 years (range 1 to 18), and CD4 count averaged 491 (95% confidence interval [CI] 408 to 552). Sixteen people were taking a protease inhibitor, 11 each were taking a nonnucleoside or an integrase inhibitor, and 7 were taking a CCR5 antagonist.
HIV DNA (representing early reverse transcripts) could be detected in CD4-cell cytoplasm of 11 people (31%), while LTR-gag sequences (representing late reverse transcripts) could never be detected in their CD4-cell cytoplasm. CD4 slope calculated with 3 measurements over 6 months was negative in the 11 people with detectable cytoplasmic HIV DNA (average -4 cells per month, 95% CI -15 to +8). In contrast, CD4 slope was positive in the 24 people without detectable cytoplasmic HIV DNA (average slope +12 cells per month, 95% CI +3 to +20) (P = 0.04 versus HIV DNA-positive group slope).
The investigators evaluated immune activation in a subset of 20 people. The percentage of activated (CD38-positive) T cells rose in people with detectable cytoplasmic HIV DNA (average slope +0.5% per month, 95% CI -0.7 to +1.7), whereas that percentage fell in people without detectable cytoplasmic HIV DNA (average -1.3% per month, 95% CI -2.3 to -0.3) (P = 0.02 versus HIV DNA-positive group slope).
The Montpellier-Nimes collaborators observed that the 31% rate of HIV DNA detection in CD4-cell cytoplasm in aviremic patients is consistent with results reported by other groups using different assays. This signal of recent CD4-cell infection in people with an undetectable viral load correlated with a negative CD4 slope and greater CD8-cell activation.
The investigators believe their findings "argue for a role of ongoing HIV infection in the persistence of immune activation and in the impairment of immune restoration in some virologic responders." They suggested that their assay may offer a simple way to assess the potency of antiretroviral regimens, to monitor ART simplification, to determine which patients may need a stronger regimen, and to distinguish ongoing CD4-cell infection from other causes of poor CD4 gains.
Reference
1. Psomas KC, Mettling C, Reynes J, Corbeau P. Poor CD4+ T-cell restoration linked to residual HIV-1 reverse transcription under antiretroviral therapy. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-1570a.
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