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. Author manuscript; available in PMC: 2013 Sep 24.
Published in final edited form as: AIDS. 2012 Sep 24;26(15):1879–1884. doi: 10.1097/QAD.0b013e328357f5d1

Chronic immune activation and decreased CD4 counts associated with Hepatitis C Infection in HIV-1 Natural Viral Suppressors

Mohammad M Sajadi a, Roopa Pulijala a, Robert R Redfield a, Rohit Talwani a
PMCID: PMC3772623  NIHMSID: NIHMS505977  PMID: 22824629

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 counts for many years [1, 4, 6].

We previously reported that within this NVS cohort, patients with active HCV infection had lower CD4 counts and CD4 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 co-infected patients, and if this correlated with CD4 cell count decline.

METHODS

Study patients

The NVS cohort has been described in detail elsewhere[1–3].Briefly, after informed consent was obtained, NVS patients had to be confirmed HIV-1 positive by Western Blot and proviral DNA, and have demonstrated viral loads <400 copies/ml for a 2 year time period without the use of antiretroviral therapy (one viral load > 400 copies/ml in a 2 year period was allowed provided the subsequent values were < 400 copies/ml). All patients in the NVS cohort were required to have a Hepatitis C antibody or PCR test performed. For those with a positive Hepatitis C antibody, a follow-up PCR (quantitative or qualitative) was required.

Several cohorts were created for comparison with the NVS cohort. These included HIV/HCV negative individuals, HCV mono-infected patients, and non-NVS HIV and HIV/HCV coinfected patients. These cohorts were matched closely for race but not other parameters. HIV/HCV negative individuals were exclusively non-IDU, while the majority (88%) of the HCV monoinfected had a history of IDU.

Demographic and laboratory data collected

The demographic data collected included the following: Age, sex, race, date of diagnosis of HIV, and risk factor for HIV. For the NVS earliest and latest CD4 count, and mean CD4 count, CD4%, and CD4/CD8 ratios were recorded. ALT and APRI score were calculated based on available data closest to date of sample tested for immune activation. HIV-1 proviral copy number was performed as described previously[2]. Flow cytomtery was performed by using FACSCalibur flow(BD Biosciences, San Jose, CA), with gating for CD3, CD8, HLA-DR, and CD38. PBMCs were stained by using CD3 PerCP, CD8 APC, CD38 PE, and HLA-DR FITC (BD Biosciences, San Jose, CA). All of the dyes were used according to manufacturer’s specifications and optimized according to the experiment. Data was analyzed by using FlowJo software (Ashland, OR).

Statistical analysis and definitions

“Chronic HCV infection” was defined as demonstratinga positiveplasma PCR for HCV. Those “without chronic HCV infection” were defined as those having a negative HCV antibody, or a positive HCV antibody with a negative HCV PCR. CD3+ CD8+ cells with dual expression of HLA-DR+ and CD38+ were defined as activated.

For data with normal distribution Student’s t test was performed; otherwise, the Mann-Whitney test was used. Fischer’s exact test was used for contingency table testing. All p values were two-tailed and considered significant if < .05. All data were analyzed with GraphPad Prism software (San Diego, CA).

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 2 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 NVS 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 controls 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 percent of CD38+ HLA-DR+ CD8 cells (p=.004). NVS without chronic HCV had a statistically significantly elevated %CD38+ HLA-DR+ CD8 cells compared to HIV/HCV negative controls (p=.003), and NVS with chronic HCV had a statistically significant elevated %CD38+ HLA-DR+ cells compared to those with HCV monoinfection (p=.006). Overall, HCV-negative NVS, HCV monoinfected, and HIV/HCV negative patients had lower levels 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 Figure 1A.

Figure 1.

Figure 1

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Effect of HIV and HCV on percent of activated CD8 cells. Percentages are given as proportion of CD38+ and HLA-DR+ cells among all CD3+ CD8+ cells. A) Percent of CD38+HLADR+ cells among normal controls, HCV monoinfected, NVS without chronic HCV, NVS with chronic HCV, HIV monoinfected, and HIV/HCV dual infected patients. The association of HCV infection with immune activation within the NVS is seen when comparing those with or without chronic HCV infection (p=.004). The association of HIV infection with immune activation in the NVS are demonostrated when comparing NVS without chronic HCV to HIV/HCV negative controls, or NVS with chronic HCV to HCV monoinfected controls (p=.003 and .006, respectively). B) Effect of sex, IDU status, HLA-B57 status, or HIV-1 viral blip >400 copies/ml on percent of activated CD8 cells. There was no statistically significant effect of sex, IDU status, HLA-B57 status, or HIV-1 viral blip on the percent of activated CD8 cells. HCV=Hepatitis C virus. IDU=injection drug use. NVS=HIV-1 infected individuals with HIV-1 viral loads <400 copies/ml without therapy.

Within the NVS, levels of immune activation did not correlate with sex, IDU history, HLA-B57 status, or viral blips >400 HIV-1 RNA copies/ml (p=.30, p=21, p=.16, and p=.09, respectively) (Figure 1B). Among NVS with chronic HCV, there was no correlation between %CD38+ HLADR+ CD8 cells and HCV viral load, ALT, or APRI score (data not shown).

HIV-related Parameters in the NVS based on HCV status

Within the NVS cohort, individuals without chronic HCV had a statistically significant elevation in mean CD4 count (928 cells/ul) compared to those NVS with chronic HCV (766 cells/ul) (p=.038).This correlation of CD4 count with HCV status was statistically significant for earliest recorded CD4 count (p=.01) and there was a trend toward significance with the most recent CD4 count as well (p=.058). There was a similarly statistically significant elevation in the mean CD4% and mean CD4/CD8 ratio in those without chronic HCV compared to the chronic HCV group (p=.008 and p=.048, respectively). We found no correlation between chronic HCV status and HIV-1 viral blips to >400(p=1). In patients with at least 6 available data points, there was no correlation between chronic HCV status and CD4 slope, CD4% slope, or CD4/CD8 ratio slope (p=.37, p=.83, and p=.37, respectively).

Correlation between CD4 count and CD8 immune activation

Among all NVS, there was a direct correlation between mean CD4 count, mean CD4%, and mean CD4/CD8 ratio with %CD38 + HLA-DR+ CD8 cells [p=.0018 (r2=.17); p=.0069 (r2=.13);and p=.0014 (r2=.21), respectively] (Figure 2). On sub-analysis, this correlation between immune activation and CD4 counts held more often true with the NVS with chronic HCV, with correlations with latest CD4 count (p=.003), mean CD4 count (p=.003), and mean CD4/CD8 ratio (p=.015), than those NVS without chronic HCV (p=.022 for latest CD4 count only).

Figure 2.

Figure 2

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Correlation between activated CD8 cells and mean CD4 count, CD4%, and CD4/CD8 ratio in the NVS. X axis represents percentages of CD38+ and HLA-DR+ cells among all CD3+ CD8+ cells. Y axis represents mean CD4 cells count in cells/ul, mean CD4 percentile, or mean CD4/CD8 ratio A) Correlation between mean CD4 count and percent activated CD8 cells (p=.0018, r2 =.17). B) Correlation between mean CD4 % and percent activated CD8 cells (p=.0069, r2 =.13). C) Correlation between mean CD4/CD8 ratio and percent activated CD8 cells (p=.0014, r2 =.21).

DISCUSSION

This study suggests a relationship between immune activation, HCV infection, and CD4 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=.004). This difference could not be explained by any differences between the groups, including sex and HLA-status. While 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%, than NVS without HCV. In this larger study, we have found lower mean CD4 count, mean CD4%, 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 count on record. CD4 count slope was not significantly difference 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 count between these 2 groups occurs 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 counts [10–14]. As this effect of HIV on immune activation can be substantial, the contributory effect of other co-pathogens such as HCV can be masked, unless in situations where 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. Though there is not 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. have suggested that abnormal gut translocation as a result of HIV infection is poorly controlled in HCV co-infected patients [32]. 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, though this must be corroborated by larger studies.

In this study, the observation that chronic HCV viremia is associated with both decreased CD4 counts and elevated levels of immune activation, suggests that the mechanism for reduced CD4 counts are related to immune activation, similar to findings reported by Gonzalez et al [29]. In addition, because the CD4 loss appears to occur early and stabilize, it is possible that with successful HCV treatment may decrease immune activation thereby increasing CD4 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.

While this study utilized a large cohort of individuals with HIV suppression and adds to the body of literature of HIV/HCV co-infection, 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 used 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 counts, CD4%, and CD4/CD8 ratio than NVS without chronic HCV infection. The difference in CD4 count appeared to occur early with no difference in the CD4 slopes between groups. Immune activation directly correlated with mean CD4 count, CD4%, and CD4/CD8 ratio. Further studies will be needed to see if HCV treatment leads to lower immune activation levels and rise in CD4 counts in these patients.

Acknowledgments

Funding: M.M.S. supported by award number 5K23AI084580 -02

We would like to thank members of the NVS cohort and Becky Boyce, RN, the study coordinator.

Footnotes

Conflict of Interest: M.M.S., R.T., R.P. and R.R.R. report no conflict of interests.

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