A new paper in the journal AIDS Research and Human Retroviruses reports that the majority of CD4 T cells harboring latent HIV infection are specific for HIV antigens (as opposed to other common antigens such as PPD, CMV or influenza). Conducted by Ashwini Shete and colleagues from the National AIDS Research Institute in India, the study investigated the capacity of a variety of antigens to stimulate HIV replication in CD4 T cells from people with HIV (both on and off ART). In untreated individuals, Env and Pol antigens invoked significantly more HIV expression than other HIV and non-HIV antigens. In a cohort of 18 individuals on ART, HIV replication was induced significantly more frequently after stimulation with Env, Pol and Gag compared to other HIV and non-HIV antigens. Notably, a minority of participants did show evidence of lower-frequency infection of cells specific for peptides from PPD, influenza, EBV and CMV. The findings echo and extend those reported in 2002 by Audreya Demoustier and colleagues (available in full text online), which documented preferential stimulation of latent HIV with a less diverse array of viral antigens (p24 and Nef).
As the authors note, these data imply that therapeutic HIV vaccines—when combined with ART—may have the potential to both activate latent viral reservoirs and bolster the immune response against the virus. The data further suggest that therapeutic HIV vaccine candidates will need to include a broad array of HIV antigens if the goal is to maximize the activation of latent HIV.
Coincidentally, the first published study to address the impact of therapeutic vaccination on the latent HIV reservoir just appeared online in the journal AIDS. Deborah Persaud and colleagues analyzed data from a pediatric trial of MVA and Fowlpox-based therapeutic HIV vaccines, finding evidence of a significant but transient reduction in the number of latently infected CD4 T cells. The vaccines contained HIV env, gag, tat, rev, nef and reverse transcriptase genes; immunizations were with MVA at weeks 0 and 4 and Fowlpox at weeks 8 and 24 (although only 11 of the 18 study participants received the final Fowlpox boost due to an interruption in supply of the vaccine). A significant reduction in the frequency of latently infected CD4 T cells was demonstrated at week 40, but was no longer detectable by week 72 of follow up. The authors state: “This effect may result from enhanced targeting of latently infected CD4 T cells by vaccine-induced HIV-specific immune responses upon exiting the latent reservoir during activation; or by direct reactivation of HIV-specific memory CD4 T cells harboring latent HIV with therapeutic immunizations, and warrants evaluation in other studies.” An ongoing trial named EraMune02 is currently exploring the impact of therapeutic vaccination on HIV reservoirs in greater detail.
AIDS Res Hum Retroviruses. 2011 Sep 22. [Epub ahead of print]
Shete A, Thakar M, Singh DP, Gangakhedkar RR, Gaikwad A, Pawar J, Paranjape RS.
National AIDS Research Institute, Immunology, 73 G block MIDC, Bhosari, Pune, India, 411026.
Therapeutic vaccinations using Human Immunodeficiency Virus (HIV) antigens in HIV infected patients on antiretroviral therapy (ART) have so far been attempted with the purpose of inducing CTL response. However they can also be useful as a strategy for activation of latent HIV reservoir which is thought to be mainly comprised of latently infected HIV specific memory CD4 cells, eventually leading to elimination of the virus. The present study was carried out to explore ability of different HIV antigens to activate HIV replication as assessed by intracellular P24 detection as well as to induce T cell responses in terms of cytokine expression by flow cytometry after stimulation of PBMCs from HIV infected patients. HIV antigens were found to be able to activate most of the CD4 T cells harboring proviral DNA. HIV-1 Pol and Env were responsible for induction of higher HIV replication in terms of both magnitude and frequency followed by Gag and Nef. As against this, Pol and Env contributed to less number of polyfunctional CD8 cells desirable for elimination of HIV infected cells in comparison to Gag and Nef. Thus HIV antigens may provide strategy for activation of latent reservoir. It was observed that HIV replication started as early as half an hour after in vitro activation indicating stringent need for maintaining effective concentrations of antiretroviral drugs to prevent further spread of HIV during this process. HIV infected cells were found to be responsible for higher IL-10 secretion after activation, which could also serve as one of the reasons for suppressed CD8 responses to Pol and Env as more number of HIV infected CD4 cells would be secreting IL-10 in response to these antigens. Since IL-10 blockade helped in improving immune responses in terms of cytokine secretion, it should be considered in settings of therapeutic vaccination to improve CTL responses, which will ultimately limit persistence of viral reservoir.
AIDS. 2011 Sep 13. [Epub ahead of print]
Persaud D, Luzuriaga K, Ziemniak C, Muresan P, Greenough T, Fenton T, Blackford A, Ferguson K, Neu N, Cunningham CK.
aJohns Hopkins University School of Medicine, Baltimore, MD, United States bPediatrics and Molecular Medicine, University of MA Medical School, Worcester, MA, United States cStatistical and Data Analysis Center, Harvard School of Public Health, Boston, MA, United States dColumbia University Medical Center, NY, United States eDuke University Medical Center, Durham, NC, United States.
Therapeutic HIV vaccinations may alter the size of the resting memory CD4+ T-cell latent HIV reservoir as HIV establishes latency when memory responses are formed, including those towards HIV. Alternatively, latently infected CD4+ T cells maybe killed while exiting the reservoir upon activation.
The effect of therapeutic immunization with modified vaccinia Ankara and Fowlpox-based HIV vaccines on the latent reservoir was examined in 19 young adults who were receiving effective antiretroviral therapy. Correlations between size of the reservoir (measured in infectious units per million [IUPM]) resting CD4+ T cells and HIV-1 specific immune responses, including immune activation were examined. Decay of the reservoir was assessed using random-effects model.
A modest transient decrease in the size of the reservoir was observed at week 40 (mean -0.31-log10 IUPM [95% CI: -0.60 to -0.03; P = 0.03) following HIV vaccinations. The estimated half-life (T1/2) of the reservoir during the 40 weeks following vaccination was 9.8 months and statistically different from zero (P = 0.02), but 35.3 months and not different from zero (P = 0.21) over 72 weeks of study. Latent reservoir size at baseline was not correlated with HIV-specific CD4+, CD8+ responses or immune activation, but became correlated with CD4+ IFNγ (r = 0.54, P = 0.02) and IL-2- responses at six weeks post immunization (r = 0.48, P = 0.04).
Therapeutic HIV-1 vaccinations led to a transient increase in decay of latently infected CD4+ T cells. Further studies of therapeutic HIV vaccines may provide important insights into facilitating decay of the latent reservoir.