Abstract
Although antiretroviral therapy (ART) can suppress HIV-1 replication sufficiently to eliminate measurable plasma viremia, infected cells remain and ensure viral recrudescence after discontinuation of ART. We used a macaque model of HIV-1/AIDS to evaluate the location of infected cells during ART. Twelve macaques were infected with RT-SHIVmne, a SIV containing HIV-1 reverse transcriptase, conferring sensitivity to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Ten to fourteen weeks post-infection, 6 animals were treated with 3 or 4 antiretroviral drugs for 17-20 weeks; 6 control animals remained untreated. Viral DNA (vDNA) and RNA (vRNA) were measured in peripheral blood mononuclear cells (PBMC) and at necropsy in multiple tissues by quantitative PCR and RT-PCR. The majority of virally infected cells were located in lymphoid tissues with variable levels in the gastrointestinal tract of both treated and untreated animals. Tissue viral DNA levels correlated with week 1 plasma viremia, suggesting that tissues that harbor proviral DNA are established within the first week of infection. PBMC vDNA levels did not correlate with plasma viremia or tissue levels of vDNA. vRNA levels were high in lymphoid and gastrointestinal tissues of the untreated animals; animals on ART had little vRNA expressed in tissues and virus could not be cultured from lymph node resting CD4+ cells after 17-20 weeks on ART, indicating little or no ongoing viral replication. Strategies for eradication of HIV-1 will need to target residual virus in ART suppressed individuals, which may not be accurately reflected by frequencies of infected cells in blood.
Highlights
Current treatment for HIV infection is not curative
The range in peak and postacute levels of plasma viremia made it possible to evaluate potential correlations between these levels of plasma viremia and viral RNA (vRNA) and Viral DNA (vDNA) levels in tissues taken at necropsy
Because 3 drugs did not completely suppress high plasma viremia levels, treatment of 4 animals with TFV, FTC, EFV, and the integrase inhibitor L-870812 was initiated at week (GV08 and GN19) or week (GG45 and GV40) until euthanasia and necropsy after 17-18 weeks on antiretroviral therapy (ART) (30-32 weeks post-infection)
Summary
Current treatment for HIV infection is not curative. plasma viremia can be suppressed to very low or undetectable levels in HIV-infected individuals by effective antiretroviral therapy (ART), infected cells remain in the body and treatment discontinuation is almost always associated with viral recrudescence and the risk of disease progression [1,2,3,4,5]. SIV or SHIV infection of macaques recapitulates key aspects of human HIV-1 infection including progressive disease with clinically significant immunodeficiency and death from opportunistic infections or neoplasms despite the development of antiretroviral immune responses, such as neutralizing antibodies and cytotoxic T lymphocytes against the virus. While SIV shares a high degree of structural and sequence identity to HIV-1, the differences are significant enough to limit the use of some therapies in SIV-infected macaque models. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are only active against reverse transcriptases (RT) from HIV-1 and not those from HIV-2 or SIV [20] To overcome this limitation, the RT coding region of different SIV clones has been replaced with that of HIV-1 to produce RT-SHIVs, which can be targeted by RT inhibitors, including NNRTIs, for use in macaque studies [21,22]
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