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Chronic immune activation and decreased CD4 cell counts associated with hepatitis C infection in HIV-1 natural viral suppressors
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AIDS: 24 September 2012
Sajadi, Mohammad M.; Pulijala, Roopa; Redfield, Robert R.; Talwani, Rohit
Institute of Human Virology at the University of Maryland School of Medicine, Baltimore, Maryland, USA.
"NVS [natural viral suppressors] patients with chronic HCV infection had elevated levels of immune activation (CD38-positive HLA-DR-positive CD8 cells) and lower mean CD4 cell counts, CD4 percentage, and CD4/CD8 ratio than NVS without chronic HCV infection. The difference in CD4 cell count appeared to occur early with no difference in the CD4 slopes between groups. Immune activation directly correlated with mean CD4 cell count, CD4 percentage, and CD4/CD8 ratio. Further studies will be needed to see if HCV treatment leads to lower immune activation levels and rise in CD4 cell counts in these patients."
"This study suggests a relationship between immune activation, HCV infection, and CD4 cell count in the NVS, a cohort of HIV-1-infected individuals who can control HIV replication to extremely low levels. Overall, the NVS had levels of immune activation between normal controls and HIV-infected individuals agreeing with previous findings [8]. The effect on HIV infection on immune activation can be seen when comparing the NVS with chronic HCV to HCV-monoinfected patients, or when comparing NVS without chronic HCV with HIV/HCV-negative controls. However, what is noteworthy is that an effect of HCV infection can be seen as well."
Abstract
We have established a cohort of natural viral suppressors (NVS) who can suppress HIV-1 replication to less than 400 copies/ml in the absence of therapy (similar to Elite Controllers/Elite Suppressors). Of the 59 patients currently in the NVS cohort, 45.8% have chronic hepatitis C virus (HCV) infection, thereby presenting a unique opportunity to study immune activation and the interaction between HCV and HIV. NVS with chronic HCV infection had elevated levels of immune activation (CD38-positive HLA-DR-positive CD8 cells) compared to NVS without chronic HCV (P = 0.004). The increased levels of immune activation were not associated with sex, HLA B57 status, or injection drug use use. NVS patients with chronic HCV had lower mean CD4 cell counts, CD4 percentage, and CD4/CD8 ratios than NVS without chronic HCV infection (P = 0.038, P = 0.008, and P = 0.048, respectively). The difference in CD4 cell count appeared to occur early in HIV infection with no difference observed in CD4 slopes between groups. Among all NVS, there was a direct correlation between mean CD4 cell count, mean CD4 percentage, and mean CD4/CD8 ratio with percentage of CD38+ HLA-DR+ CD8 cells (P = 0.0018; P = 0.0069; and P = 0.0014, respectively). This study suggests a relationship between HCV infection, immune activation, and CD4 cell counts in the NVS, with chronic HCV infection associated with lower CD4 cell counts and higher levels of immune activation. Further studies are needed to determine if successful HCV treatment lowers immune activation levels and/or increases CD4 cell counts in these patients.
Introduction
Natural viral suppressors (NVS) are HIV-infected patients who have the ability to naturally suppress HIV-1 to undetectable levels in the absence of therapy [1-3]. Multiple factors appear to contribute to this natural suppression [4]; however, the precise mechanisms remain poorly understood. Recently, some specific immune defects have been described in these patients [5], however, these individuals still maintain normal CD4 cell counts for many years [1,4,6].
We previously reported that within this NVS cohort, patients with active hepatitis C virus (HCV) infection had lower CD4 cell counts and CD4 cell count percentages than NVS without HCV infection [3]. Given the substantial increase in the number of patients in this cohort, we sought to verify this earlier work, determine if markers of immune activation were increased in the coinfected patients, and if this correlated with CD4 cell count decline.
Discussion
This study suggests a relationship between immune activation, HCV infection, and CD4 cell count in the NVS, a cohort of HIV-1-infected individuals who can control HIV replication to extremely low levels. Overall, the NVS had levels of immune activation between normal controls and HIV-infected individuals agreeing with previous findings [8]. The effect on HIV infection on immune activation can be seen when comparing the NVS with chronic HCV to HCV-monoinfected patients, or when comparing NVS without chronic HCV with HIV/HCV-negative controls. However, what is noteworthy is that an effect of HCV infection can be seen as well. There was a difference in the percentage of CD38-positive HLA-DR-positive CD8+ cells within the NVS group, with the chronic HCV group having a median of 25.6% compared to 15.1% activated CD8+ cells in those without chronic HCV negative (P = 0.004). This difference could not be explained by any differences between the groups, including sex and HLA-status. Although there was a statistically significant higher IDU rate in the chronic HCV NVS compared to the chronic HCV-negative NVS, IDU status by itself did not correlate immune activation. Thus, IDU was a confounder for the true marker, which is chronic HCV infection.
We had previously reported that in this cohort, patients with chronic HCV (defined by a positive blood PCR) had lower CD4 and CD4 percentage, than NVS without HCV. In this larger study, we have found lower mean CD4 cell count, mean CD4 percentage, and mean CD4/CD8 ratio in the NVS with chronic HCV compared to those without chronic HCV infection. The difference in CD4 cell count was also noted when comparing the earliest CD4 cell count on record. CD4 cell count slope was not significantly different between those who had chronic HCV and those without chronic HCV. The estimated date of acquisition of HCV infection in this group predates acquisition of HIV by one or more decades [3,9]; thus, in most of these patients, chronic HCV infection was present at the time of HIV infection. Taken together, this suggests that the difference in CD4 cell count between these two groups occur early in infection (and that the presence of chronic HCV may affect the course of acute HIV infection in the NVS), as subsequently the rate of CD4 change is not significantly affected.
In chronic HIV infection, immune activation is felt to play a role in the mechanism of CD4 decline, as patients treated with HAART demonstrate decreased levels of immune activation and a corresponding rise in CD4 cell counts [10-14]. As this effect of HIV on immune activation can be substantial, the contributory effect of other copathogens such as HCV can be masked, unless in situations in which the HIV is controlled, such as in the NVS or patients undergoing HAART therapy. There is evidence that HCV infection can affect the course of HIV infection. Specifically, studies have shown that the presence of HCV can blunt the CD4 recovery. Although there is no agreement on all studies whether HCV coinfection leads to decreased number of CD4 cell recovery [15-23], there does appear to be a delayed CD4 reconstitution associated with HIV/HCV-coinfected patients undergoing HAART therapy [24-27]. In addition, HCV infection has been cited as a risk factor for developing an AIDS-defining illness [28].
HIV/HCV-coinfected patients have been shown to have increased levels of CD8 activation compared to HIV-monoinfected patients [29-31]. In one study, HCV treatment in HIV-infected patients on a stable HAART regimen led to decreased levels of immune activation (compared to pre-HCV treatment immune activation levels) [29]. Sandberg et al.[32] have suggested that abnormal gut translocation as a result of HIV infection is poorly controlled in HCV-coinfected patients. The impaired liver function and thus impaired microbial clearance as a result of HCV infection is thought to exacerbate immune activation. The data in this study do not support this, as elevated activation levels were not associated with increased ALT or APRI scores, although this must be corroborated by larger studies.
In this study, the observation that chronic HCV viremia is associated with both decreased CD4 cell counts and elevated levels of immune activation suggests that the mechanism for reduced CD4 cell counts are related to immune activation, similar to findings reported by Gonzalez et al.[29]. In addition, as the CD4 loss appears to occur early and stabilize, it is possible that with successful HCV treatment may decrease immune activation, thereby, increasing CD4 cell counts. This may factor into deciding whether these patients should be treated, especially if larger studies show that the chronically high levels of activation could put patients at risk for other complications.
The NVS cohort presents an ideal opportunity to study the effects of HCV on HIV. At baseline, NVS patients have very low HIV-1 viral loads, and levels of immune activation between healthy controls and non-NVS HIV-infected patients. In addition, the NVS lack the widespread immune dysfunction and disease seen in typical HIV-infected patients.
Although this study utilized a large cohort of individuals with HIV suppression and adds to the body of literature of HIV/HCV coinfection, it has certain limitations. This study did not use a HIV/HCV-negative control group that matched IDU risk factor; however, the similar results between this group and the HCV monoinfected (majority IDU) makes it unlikely that IDU in itself could affect immune activation levels. This study also included use of a majority African-American cohort; thus, other studies will have to be done to verify the results and generalizability of these findings.
Conclusion
NVS patients with chronic HCV infection had elevated levels of immune activation (CD38-positive HLA-DR-positive CD8 cells) and lower mean CD4 cell counts, CD4 percentage, and CD4/CD8 ratio than NVS without chronic HCV infection. The difference in CD4 cell count appeared to occur early with no difference in the CD4 slopes between groups. Immune activation directly correlated with mean CD4 cell count, CD4 percentage, and CD4/CD8 ratio. Further studies will be needed to see if HCV treatment leads to lower immune activation levels and rise in CD4 cell counts in these patients.
Results
Patient characteristics
We have established a cohort of 59 NVS patients, of which 45.8% have chronic HCV infection. We further characterized the NVS cohort into those with chronic HCV and those without chronic HCV infection. The only statistically significant difference between the two groups was IDU as a risk factor for HIV, with 85.7% in the HCV positive versus 28.1% in the HCV negative (P = .0001). The demographics of these two groups within the NVS cohort are shown in Table 1. Of note, 10 patients who had positive HCV ELISAs were PCR negative suggesting that they had cleared infection (one of these patients had cleared with HCV therapy). Excluding the one patient who received HCV therapy, the spontaneous HCV clearance rate in the NVS is 25%, slightly higher than our earlier findings [3,7].
Immune activation in the natural viral suppressors and controls
Immune activation was measured in the NVS (n = 53), HIV/HCV-negative controls (n = 12), HCV-monoinfected (n = 10), HIV-monoinfected (n = 9), and dual HIV/HCV-infected patients (n = 4). Immune activation was lowest in the HIV/HCV-negative and HCV-monoinfected controls, followed by sequentially higher levels in the NVS without chronic HCV, NVS with chronic HCV, and then HIV and HIV/HCV control groups. Within the NVS cohort, level of immune activation correlated with chronic HCV status, with those NVS with HCV infection having a statistically significant elevation in percentage of CD38+ HLA-DR+ CD8 cells (P = 0.004). NVS without chronic HCV had a statistically significantly elevated percentage of CD38+ HLA-DR+ CD8 cells compared to HIV/HCV-negative controls (P = 0.003), and NVS with chronic HCV had a statistically significant elevated percentage of CD38+ HLA-DR+ cells compared to those with HCV monoinfection (P = 0.006). Overall, HCV-negative NVS, HCV monoinfected, and HIV/HCV negative patients had lower levels of percentage of CD38+ HLA-DR+ CD8 cells compared to NVS with HCV, or dual HIV/HCV-infected individuals. A summary of the above is shown in Fig. 1a.
Within the NVS, levels of immune activation did not correlate with sex, IDU history, HLA-B57 status, or viral blips more than 400 copies/ml HIV-1 RNA (P = 0.30, P = 0.21, P = 0.16, and P = 0.09, respectively) (Fig. 1b). Among NVS with chronic HCV, there was no correlation between percentage of CD38+ HLA-DR+ CD8 cells and HCV viral load, ALT, or APRI score (data not shown).
HIV-related parameters in the natural viral suppressors based on hepatitis C virus status
Within the NVS cohort, individuals without chronic HCV had a statistically significant elevation in mean CD4 cell count (928 cells/μl) compared to those NVS with chronic HCV (766 cells/μl) (P = 0.038). This correlation of CD4 cell count with HCV status was statistically significant for earliest recorded CD4 cell count (P = 0.01) and there was a trend toward significance with the most recent CD4 cell count as well (P = 0.058). There was a similarly statistically significant elevation in the mean CD4 percentage and mean CD4/CD8 ratio in those without chronic HCV compared to the chronic HCV group (P = 0.008 and P = 0.048, respectively). We found no correlation between chronic HCV status and HIV-1 viral blips to more than 400 (P = 1.0). In patients with at least six available data points, there was no correlation between chronic HCV status and CD4 slope, CD4 percentage slope, or CD4/CD8 ratio slope (P = 0.37, P = 0.83, and P = 0.37, respectively).
Correlation between CD4 cell count and CD8 immune activation
Among all NVS, there was a direct correlation between mean CD4 cell count, mean CD4 percentage, and mean CD4/CD8 ratio with percentage of CD38+ HLA-DR+ CD8 cells [P = 0.0018 (r2 = 0.17); P = 0.0069 (r2 = 0.13); and P = 0.0014 (r2 = 0.21), respectively] (Fig. 2). On subanalysis, this correlation between immune activation and CD4 cell counts held more often true with the NVS with chronic HCV, with correlations with latest CD4 cell count (P = 0.003), mean CD4 cell count (P = 0.003), and mean CD4/CD8 ratio (P = 0.015), than those NVS without chronic HCV (P = 0.022 for latest CD4 cell count only).
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