HIV "elite controllers" in a large women's study were found to still have low-level plasma HIV viral load, which could contribute to persistent immune activation and inflammation, researchers reported at the XIX International AIDS Conference (AIDS 2012) last month in Washington, DC. A series of related studies showed that immune activation was greater in people with HIV and hepatitis C coinfection, and that HIV controllers were also more likely to clear HCV -- though it is not clear why.

A growing body of evidence suggests that chronic immune activation and inflammation play a role in a variety of non-AIDS conditions, ranging from cardiovascular disease to neurocognitive impairment, in the aging HIV positive population.

Several studies presented at AIDS 2012 looked at the causes and consequences of inflammation in people with HIV. Another set of studies focused on immune activation in so-called elite controllers -- individuals who are able to naturally maintain undetectable viral load without antiretroviral therapy (ART) -- and in HIV/HCV coinfected people.

Alan Landay and Seema Desai from Rush University Medical Center and colleagues (abstract THPE039) assessed residual viral replication in blood plasma and cervical-vaginal fluid from elite controllers in the Women's Interagency HIV Study (WIHS), the largest cohort of HIV positive and at-risk HIV negative women in the U.S.

The analysis included 32 natural HIV controllers, defined as having plasma HIV RNA < 80 copies/mL in the absence of ART for at least 2 years. These women were matched with 31 participants who maintained undetectable viral load on combination ART for at least 2 years. Low-level viral load was measured in plasma and cervical-vaginal fluid using a sensitive assay with a lower limit of detection below 3.5 copies/mL.

The researchers detected persistentlow-level viral replication in all elite controllers, and in fact their plasma viral load was significantly greater on average than that of non-controllers on suppressive ART. HIV RNA levels in cervical-vaginal fluid were "essentially undetectable" in both groups, suggesting low risk of sexual transmission.

"[P]ersistent low-level HIV RNA in the plasma of elite controllers suggests a mechanism for increased levels of immune activation that have been seen in these subjects," the WIHS investigators concluded. This persistent low-level viral replication may contribute to CD4 T-cell immune decline over time, indicating that even elite controllers may benefit from combination ART, they suggested.

HIV positive people coinfected with HCV tend to experience faster liver disease progression than patients with hepatitis C alone. While the biological mechanisms underlying accelerated liver disease are not fully understood, some experts have suggested that increased inflammation and immune activation associated with 2 persistent viral infections may play a role.

Another WIHS analysis by the Rush University team (abstract THPE027) found that HIV/HCV coinfected elite controllers showed more CD8 T-cell immune activation than HIV negative women with undetectable HCV RNA, although less than women with uncontrolled HIV replication. HIV elite controllers with detectable HCV RNA had decreased CD8 T-cell interferon-gamma responsiveness, which the reseachers suggested"may be important to the regulation of viral infections in these patients."

Aimee Hodowanec, also with Landay's team at Rush University, and colleagues (abstract MOPE011) compared expression of immune activation markers on CD4 T-cells in 59 age- and sex-matched patients (73% men) with HIV alone, HCV monoinfection with chronic hepatitis C, HIV/HCV coinfection with chronic hepatitis C, or coinfection with HCV clearance.

CD38+HLADR+ expressionwas significantly greater in HIV/HCV coinfected people with chronic hepatitis C compared with either HCV monoinfected people or coinfected people who had cleared HCV. Total CD4+CD38+ and CD4+CD38+HLADR- expression was significantly higher in coinfected people with HCV clearance than in HCV monoinfected people, and was significantly higher in HIV monoinfection compared with HCV moninfection.

In contrast to previously reported increased CD8 activation in people with poorly controlled HIV, however, "there were no differences in CD8 activation in our populations with undetectable HIV viremia," the researchers noted.

There was no consistent correlation between immune activation and liver fibrosis stage (as estimated by transient elastometry, or FibroScan) based on HIV and HCV infection status, though people with mild-to-moderate fibrosis appeared to have overall lower levels of CD4 immune activation markers.

Immune activation in HIV/HCV coinfected people with well-controlled HIV "appears to arise from chronic HCV viremia," the researchers suggested. "Increased CD4 immune activation in patients with longstanding HIV/HCV coinfection with chronic hepatitis C may contribute to amplified inflammatory responses, such as increased IL-10 production, that may lead to deleterious immune exhaustion, having an impact beyond known accelerated liver fibrosis." However, they added, hepatitis C treatment that leads to sustained HCV clearance may reduce immune activation and inflammatory responses.

Finally, Alice Asher from the University of California at San Francisco and colleagues (abstract WEAX0105) explored why HIV controllers (here defined as maintaining HIV RNA < 2000 copies/mL in the absence of ART) are also more likely to spontaneously clear HCV.

Looking at nearly 300 participants in the SCOPE (Study of the Consequences of Protease Inhibitor Era) trial, they compared the proportion of HIV controllers and non-controllers with serological evidence of HCV clearance (that is, HCV antibodies but not HCV RNA) and assessed whether HLA-B57 status explains the greater likelihood of HCV clearance in HIV controllers. HLA-B57 -- the major histocompatibility class I gene -- is "highly enriched," or present at higher levels, in HIV controllers, and has also been linked to spontaneous HCV clearance.

The researchers found that HIV controllers were indeed significantly more likely than HIV non-controllers to experience spontaneous HCV clearance (58% vs 38%, respectively,) and that HIV controllers were more likely than non-controllers to have HLA-B57 (33% vs 10%). However, HLA-B57 was not significantly associated with HCV clearance overall, and there was no evidence that HCV clearance was more common among HLA-B57 positive than HLA-B57 negative HIV controllers.

"HIV controllers are more likely to spontaneously clear HCV than HIV non-controllers even when controlling for HLA-B57 status," they concluded. "Immunologic factors other than HLA-B57 must contribute to the control of HIV and HCV in HIV controllers. Identifying these factors may support the development of novel treatments for and effective vaccines against both viruses."

By Liz Highleyman

References

A Landay, E Golub, S Desai, et al. Low level viral load detection in blood and mucosal sites in elite controllers and HAART suppressed women enrolled in the Women's Interagency HIV Study (WIHS). XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract THPE039.

S Desai, A Landay, M Glesby, et al. HCV viremia affects immune phenotypes in Elite controllers of HIV infection - A Women's Interagency HIV Study. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract THPE027.

A Hodowanec, KE Brady, W Gao, et al. Differences in CD4+ T cell immune activation in HIV, hepatitis C (HCV) and HIV/HCV co-infection are influenced by HIV and HCV infection status. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract MOPE011.

A Asher, G-M Santos, EK Dokubo, et al. HLAB57 does not fully explain the ability of HIV controllers to spontaneously clear hepatitis C virus (HCV) infection. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract WEAX0105.