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Persistent and Pesky: residual replicating HIV and latent reservoirs including genital secretions
Written by David Margolis, MD, University of Texas, Southwestern Medical Center
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It is now widely appreciated that for the time being we must deal with HIV as a chronic infection for several reasons: 1) the antiviral immune response, while potent, is incomplete and does not remove or eliminate all productively infected cells, 2) antiretroviral therapy, while potent, does not completely inhibit viral replication in all productively infected cells, and 3) a very small population of resting CD4 cells can be persistently infected with quiescent HIV integrated into the host genome that can be reactivated to produce replication-competent virus.
Incremental progress in the understanding of HIV persistence was reported at the 10th CROI. Deenan Pillay's group from Birmingham, UK described shedding of HIV in semen (#454). These findings were reminiscent of a presentation from the Seattle group at the 9th CROI describing HIV shedding in the GI mucosa, in which HIV was found in most specimens, despite plasma viral suppression in most subjects. In this group herpesvirus positivity explained some but not all of the cases that were HIV+. Pillay's group studied levels of HIV found in the seminal plasma. In HIV+1 men with detectable blood plasma VL not on therapy, ~30% had undetectable seminal plasma VL, ~58% had seminal plasma VL detectable at concentrations below that in their blood plasma. Thus ~12% of this cohort were "super shedders" with higher VL in the semen than the blood. 3 of 9 of these cases were found to have concomitant urethritis, but "super shedding" could not be explained in the other 6. Such people may pose a higher risk of transmitting HIV to their sexual partners.
Studying samples from 3 patients who underwent a trial of intensive antiviral therapy aimed at eradication (reported recently in JID by Kulkosky) Nunnari studied HIV-1 DNA and RNA detected in blood and seminal plasma (#455). Evolution of viral sequences in the seminal compartment was found after intensified HAART and a trial of interruption of therapy, but the plasma rebound virus never appeared in the seminal compartment. This finding was interpreted as suggesting continued but distinct evolution of HIV in the seminal compartment, similar to findings sometimes reported in the CNS. Alternatively, rebound plasma virus might have entered the seminal compartment, but constituted a minority species not yet detected.
The prostrate gland was reported to play a potential role as an HIV reservoir, particularly in transmission events (#459a). In 4 subjects, HIV RNA was detected in seminal plasma only after prostatic massage. Further study of the appearance of HIV RNA in semen after prostatic massage in treated patients with plasma VL < 50 copies/ml is needed. Clearly this phenomenon could play a role in transmission of HIV between MSMs.
(editor's note: the study authors said Hiv in the genital tract is often genetically distinct from that in the bloodstream. This variation results from differing host selection, local immune responses, and varying penetration of drugs into the genital tract. Male genital secretions are a complex mixture of cells and secretions from the testes, epidydimis, vas deferens, seminal vesicles, prostate, urethral, and paraurethral glands. Since the prostate can harbor bacterial and fungal infections, it was investigated as a reservoir for HIV.
Seven HIV+ males submitted genital secretion samples both without prostate massage and after prostate massage. Four of 7 patients were on stable ART. Four men had undetectable seminal plasma (SP) HIV RNA without prior prostate massage but then became detectable in 1-3 samples after prior prostate massage. The remaining 3/7 men had SP samples with detectable HIV RNA at all collections, which showed no correlation with prostate massage. Blood plasma HIV RNA levels measured at the start and end of the study were unchanged in all subjects except one who showed a steep decrease in blood plasma HIV RNA level from 42,102 copies/ml to <50 copies/ml. However, the SP HIV RNA levels from this subject varied greatly (3,041 to 285,732 copies/ml) but did not correlate to prior prostate massage.
The author's conclude these data suggest that the prostate is a reservoir for HIV. This has significant transmission consequences, as prostate massage resembles receptive anal intercourse in men who have sex with men. Prostate stimulation via anal intercourse could therefore increase the amount of HIV RNA in the receptive partner'' genital secretions, which could then be transmitted when he becamethe insertive partner. These data could, in part, explain the high HIV infection rates historically seen in men who have sex with men. (abs 459a, "The Prostate as a Reservoir for HIV-1", Smith, Kingery, Ignacio, Wong, Richman, Little, Univ of California, San Diego and Loma Linda Univ, CA)
Maldarelli (#466) presented findings measuring residual viremia in HAART-treated patients using the NCI's assay with a dynamic range of 106 to 1 copy of HIV RNA/ml. The single copy assay detected HIV-1 RNA in plasma from 14 of the 15 patients treated with HAART and suppressed to < 50 copies/ml (as determined by standard methods) for at least 131 days. In one patient, no HIV-1 RNA could be detected in the assay (< 0.25 copies/ml). The lowest levels of persistent viremia were present in patients on > 3 antiretroviral agents. This assay will be very useful in future studies of latency and residual replication.
Persaud (#619) presented findings from studies of children demonstrating that, with respect to latency within resting CD4 cells, children are just little adults. As in adult Studies also performed in the Siliciano laboratory, ongoing viremia that continues during effective HAART in children represents largely wild-type or archival HIV-1 rather than recently generated drug-resistant mutants. The detection of ongoing plasma virus during effective HAART does not necessarily represent impending treatment failure, or the evolution of drug resistance and does not necessarily require adjustment in the treatment regime. Studies of 22 plasma samples obtained from 12 children on suppressive HAART (median 3 yrs, range 1-6 yrs) found ongoing viremia in 8 children. Only 17% of the HIV genomic clones that could be recovered from these subjects on PI-containing HAART encoded single PI mutations; all other genomes were drug-sensitive.
Genetic studies by Frenkel (494) in plasma and PBMC samples from treated children with infrequent low-level viremia ("blips") during years of effective HAART found that plasma HIV-1 had less diversity and less divergence from the most recent common ancestor viral species when compared to PBMC populations in most subjects. This pattern suggests the intermittent expression of virus from a subset of long-lived HIV-1 infected cells. Less frequently and among subjects with frequent bouts of intermittent viremia, plasma virus showed evidence of more evolution, indicating complete cycles of viral replication, including the selection of new drug-resistant mutants.
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