ART reduces HIV reservoirs in elite controllers: implications for cure research

25 July 2013. Related: Basic science and immunology.

Matt Sharp, HIV i-Base

Researchers from the US National Institutes of Health have been studying HIV elite controllers for several years. A recent study provides new clues from this population for eradication efforts by learning more about CD4 cells that carry replication competent virus and the dynamics of viral reservoirs when ART is initiated or discontinued.

The study by Tae-Wook Chun and colleagues looked at three elite controllers and one controller and was published online in July 2013 as an ahead of print article for the Journal of Infectious Diseases. [1]

A small proportion of people (controllers) with HIV are able to control HIV replication in the absence of ART. A subset of these individuals (elite controllers) are able to maintain relatively normal CD4 counts and undetectable plasma virus levels. However, there may be low levels of HIV replication due to viral persistence, ongoing inflammation and viral evolution. The precise frequencies of CD4 T-cells carrying replication competent virus and the impact of ART on immunologic and virologic parameters in these patients are unknown.

PMBCs were collected through blood draws and leukapheresis to isolate CD4 cells at baseline, month 6 and 9, and 3 months after discontinuation of the study. Gut biopsies were performed at baseline, after 6 months on ART and 3 months after ART was stopped. Plasma viraemia was measured in quadruplicate with the Cobas Ampliprep/Cobas Taqman HIV-1 Version 2.0 (sensitive to 20 copies/mL). Quantitative co-culture tests were used to determine the frequency of infectious virus in CD4 cells. The half-life of CD4 cells carrying infectious virus was determined at baseline, month 6 and 9. HIV DNA was detected through quantitative real time PCR. Levels of immune activation were looked at in the blood and sigmoid colon. Finally, the frequency of HIV specific CD8 cells was measured.

For this study, the definition of elite controllers (subjects 1, 2 and 3) and controllers (subject 4) were those who had suppressed virus levels at <500 and <50 copies/mL respectively, with no more than one blip above these levels. Throughout the study, CD4 and CD8 percentages remained stable in all participants. In addition, the elite controllers all had undetectable plasma viraemia (<20 copies per mL) throughout the trial, and statistically no difference in residual virus (1-19 copies/mL before, during or after ARV treatment. The baseline viraemia (88.0 +/-25.9; mean +/- SD) of the controller (subject 4) became undetectable shortly after starting treatment, then returned to detectable (131.5 +/- 24.6; mean +/- SD) following ARV discontinuation.

After no replication competent virus was found in the elite controllers using standard quantitative co-culture assays (sensitive to one per million cell), more sensitive high input quantitative co-culture (37-92 replicates of the 10 x 10(6) per well was performed. After ART initiation (with raltegravir/tenofovir/FTC), replication competent virus decreased by 1 log in two elite controllers and one controller. During ART, the level of replication-competent virus was below the level of detection in all participants. Three months following discontinuation or ART, HIV viral load returned to pre-therapy levels. This showed that ART had an impact on the size of the reservoir of infected CD4 cells that carried replication-competent virus. In the elite controllers, the frequency of CD4 cells in the blood carrying HIV DNA were not detected. This is perhaps because the vast majority of the cells carry replication-defective HIV.

In 3 out of 4 subjects, immune activation markers (CD38 and HLA-DR) decreased in blood and sigmoid colon biopsies during ART and returned to pre-treatment levels after discontinuation. ART was associated with a decrease in the frequency of HIV specific CD8 cells expressing IFN-gamma and MIP-1-beta, and these responses remained low to undetectable after ART was stopped in the three elite controllers.

In this study the researchers looked a little deeper in modifying standard virologic and immunologic parameters to show that ART has a positive impact on reducing replication competent HIV in elite controllers. They suggest that low levels of viral replication in this population can contribute to the size of the reservoir despite detectable plasma viral load.

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People who have strong individual immune response to HIV are now being given a higher priority in research and may be an ideal population to help answer some of the outstanding questions about HIV reservoir sites and the role and limitations of current ART.

This study also adds to a growing number of studies suggesting that HIV controllers may benefit from ART.

The level of long-term risk from untreated HIV in this population has not yet been quantified.

Reference:

Chun T-W et al. Effect of antiretroviral therapy on HIV reservoirs in elite controllers. J Infect Dis. (2013) doi: 10.1093/infdis/jit306 First published online: July 11, 2013.
http://jid.oxfordjournals.org/content/early/2013/07/10/infdis.jit306.abstract