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Does CD8 Cell Activation Affect CD4 Cell Recovery on ART?

Greater activation of CD8 "killer" T-cells was associated with smaller gains in CD4 "helper" T-cells among people in Uganda who achieved good HIV viral load suppression on antiretroviral therapy (ART), researchers reported in the August 30, 2011, advance online edition of AIDS.

A growing body of evidence suggests that excessive immune activation and inflammation contribute to the elevated risk of non-AIDS conditions such as cardiovascular disease, neurocognitive impairment, and bone loss in people with HIV. Chronic activation is also thought to "wear out" or contribute to accelerated aging of the immune system.

Peter Hunt and Steven Deeks from the University of California at San Francisco and colleagues looked at the effect of T-cell activation on CD4 cell recovery and mortality in a resource-limited setting.

Immune activation is associated with poor CD4 cell recovery among people in resource-rich settings, the authors noted, but "little is known about its prognostic importance in resource-limited settings, where differences in host genetics, viral factors, and prevalent co-infections may modify these associations."

This prospective study included 451 HIV positive participants in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort in Mbarara who started combination antiretroviral treatment. Most (70%) were women, the median age was 34 years, the median baseline CD4 count was 135 cells/mm³, and the median baseline viral load was about 125,000 copies/mL.

Every 3 months the researchers measured viral load, CD4 cell count, and percentage of activated T-cells, indicated by the presence of the cell surface markers CD38 and HLA-DR. The median follow-up period was 24 months; 8% of participants were lost to follow-up at 3 years.

Results

• Most participants (93%) achieved plasma viral load < 400 copies/mL by 6 months and were included in further analysis.
• Higher pre-treatment CD8 T-cell activation was significantly associated with smaller CD4 cell gains at 1 year, after adjusting for sex and pre-treatment CD4 count and viral load (P=0.017).
• CD8 T-cell activation at 1 year showed a trend toward slower CD4 cell recovery, but the difference did not reach statistical significance.
• 34 participants died during follow-up, 15 of them after 6 months on ART.
• Each 10% increase in activated CD8 T-cells at month 6 on ART was associated with a 1.6-fold increased risk of death, after adjusting for pretreatment CD4 count (P = 0.048).

Based on these findings, the study authors concluded, "Higher pre-ART CD8+ T-cell activation independently predicts slower CD4+ T-cell recovery and higher persistent CD8+ T-cell activation during ART-mediated viral suppression independently predicts increased mortality among HIV-infected Ugandans."

HIV negative people living in resource-limited settings in sub-Saharan Africa are known to have a higher proportion of activated T-cells than those living in resource-rich settings, they explained in their discussion. These differences have been attributed to environmental factors such as helminth (worm) and malaria infections.

At the 2010 Conference on Retroviruses and Opportunistic Infections, Hunt's team presented earlier data from this cohort showing that Ugandans had a higher level of CD8 T-cell activation, on average, than HIV positive participants in a San Francisco cohort. The Ugandans saw a decline in CD8 cell activation after starting ART, but it remained above that of the San Francisco group.

"[W]e have established for the first time that higher persistent CD8+ T-cell activation during early viral suppression independently predicts subsequent mortality in this setting, suggesting that immune activation is a major determinant of clinical outcomes in resource-limited settings," the authors continued in their discussion. "While low pre-therapy CD4+ T-cell counts remains the strongest predictor of overall mortality in HIV-infected Ugandans, high persistent CD8+ T-cell activation during suppressive ART is a more significant predictor of deaths occurring after the first 6 months of therapy."

"We also found that higher pre-treatment [CD8+] T-cell activation and lower pre-treatment CD4+ T cell counts strongly predicted higher T-cell activation during suppressive ART," they continued. "This is an important observation as it may suggest an immunologic cost to delaying ART initiation in this setting."

"The fact that pre-treatment T-cell activation strongly predicts T-cell activation levels during suppressive ART also suggests that factors other than the extent of productive HIV replication are likely to contribute to T-cell activation both in the presence and absence of suppressive ART," the authors explained. "Studies in both resource-rich and resource-limited settings suggest that residual T-cell activation during ART-mediated viral suppression may be at least partly explained by persistently abnormal levels of microbial translocation [leakage of bacteria from the gut] and other chronic coinfections including CMV and/or other herpesviruses."

"[I]nterventions designed to further reduce immune activation in this setting should be studied," they recommended. "Given the strong relationship between lower pre- treatment CD4þ T cell count and higher residual T cell activation, these observations also support the earlier initiation of ART in this setting.

Investigator affiliations: Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, CA; Joint Clinical Research Center, Kampala, Uganda; CA Department of Health Services; Mbarara University of Science and Technology, Uganda; Massachusetts General Hospital, Harvard School of Medicine, Boston, MA.

9/6/11

Reference

PW Hunt, HL Cao, C Muzoora, SG Deeks, et al. Impact of CD8+ T Cell Activation on CD4+ T Cell Recovery and Mortality in HIV-infected Ugandans Initiating Antiretroviral Therapy. AIDS (abstract). August 30, 2011 (Epub ahead of print).