The Role of Genetics and Immune Response in Controlling HCV Infection 

By Marina Nunez, MD, PhD

Cytokine genotypes [interleukin (IL)-6, TNF-α, TGF-β, IFN-g, and IL-10] were determined in 21 HIV-positive patients presenting with acute hepatitis C who were treated for 24 weeks with IFN-α with or without ribavirin (RBV). They were classified into high, intermediate and low producers.

The authors concluded that ‘responses to IFN-α therapy are enhanced in HIV-infected patients with acute HCV carrying the IL-6 high producer genotype (+174G/G or +174G/C). This might be explained by the IL-6 mediated activation of signal transducers and activators of transcription, which has been shown to be essential for the antiviral effect of interferons and induction of anti-HCV activity in liver cells’.

Persistence of HCV after acute infection is more frequent in HIV+ compared to non-HIV subjects. US investigators evaluated the contribution of anti-HCV-specific T cell responses to the control of HCV in a cohort of HCV antibody positive individuals with and without HIV infection [2].

Patients enrolled in the study included 60 HIV+ and 34 non-HIV HCV antibody positive subjects, half in each group with chronic infection (+ HCV RNA) and half with spontaneous HCV clearance. CD4+ T cell responses were assessed via lymphoproliferative assays using HCV GT-1 core, NS3, NS4, NS5, CMV pp65, and HIV-1 p24 proteins.

HCV-specific lymphoproliferative responses were most often seen among non-HIV subjects and with spontaneous control of HCV infection. As shown in Figure 1, there were statistically significant differences in HCV-specific responses between individuals with positive and negative HCV RNA regardless of HIV status. However, when compared HIV+ and non-HIV subjects, the differences were significant only in those with spontaneous HCV clearance.

Figure 1. HCV-specific lymphoproliferative responses according to HIV and HCV status.

Interestingly, in HIV/HCV coinfected patients, low nadir CD4 counts were associated with absence of HCV-specific lymphoproliferative responses (Figure 2).

Figure 2. HCV-specific lymphoproliferative responses according to nadir CD4 counts.

In a subsequent analysis, these same authors evaluated the durability of spontaneous control of HCV viremia in 41 subjects. Within a median follow-up time of 17 months, HCV RNA became positive in 6 of 25 HIV-infected patients (24%) and in none of 16 HIV-negative subjects (p=0.03 log rank test). They also observed a negative correlation between the magnitude of viremia and CD4 counts at the time of HCV recurrence (r= -0.94; p=0.02).  HCV-specific CD4/CD8 T cell responses declined in 3 subjects at the time of the breakthrough.

In summary, with HIV infection present, a loss of HCV-specific CD4 T cells related to nadir CD4 count is observed, which translates into higher probabilities of HCV chronic infection compared to HIV-negative patients. The authors concluded also that HIV co-infection is associated with risk of HCV recurrence (recrudescence versus reinfection), which suggests that follow-up HCV VL testing in patients with spontaneous control is necessary.

Although the issue of “HCV relapse” in this context is debatable, especially because reacquisition of a new virus has not been ruled out in this study, the strong association between HCV viremia and low CD4 counts and absence of HCV-specific lymphoproliferative responses is of great interest. A clinical implication is that avoidance of low CD4 counts may preserve HCV-specific T cells, and that leads again to the question of when is the best time to start HAART in HIV-HCV coinfected patients.

In that regard, in another study presented at this meeting, after development of a Markov model of the natural history of HCV-HIV coinfection using CD4 cell counts and fibrosis stage as predictors of death, the authors concluded that earlier initiation of HAART is likely to increase life expectancy by at least 1.27 years [3].

Spanish investigators also evaluated also HCV-specific immune responses in HIV-HCV coinfected patients compared to HCV-monoinfected patients, this time in early virologic responders to therapy [4]. While in HCV-monoinfection a decline in HCV-specific T cell responses was observed as HCV RNA clearance under treatment was achieved (T cell responses dependent on continuous antigenic stimulation), the responses in HIV-HCV-coinfected patients were very low at baseline (significantly lower than in HCV-monoinfected subjects), and did not show significant variations over time.

In a different study performed by the same team, the magnitude of lymphocyte apoptosis was examined in 30 HIV-HCV coinfected patients (with positive HCV RNA) and compared to that in 31 HIV-monoinfected patients not receiving antiretroviral therapy [5].

Memory (CD45RO+) and naïve (CD45RA+CD62L+) subsets of CD4+ and CD8+ T lymphocytes, as well as their level of activation (CD38+), were similar in both groups. Coinfected patients showed significantly higher levels of apoptosis in the naïve subset of CD4+ T cells and in the naive and memory subsets of CD8+ T cells when compared to HIV-monoinfected patients.

After adjusting for age, CD4 counts and HIV-RNA levels, HCV coinfection remained significantly associated with higher levels of apoptosis in naive CD4+ T cells [b= 0.29 (95% CI 0.2-6.4); p=0.04], naive CD8+ T cells [b=0.32 (95% CI 0.53-9.2); p=0.03], and memory CD8+ T cells [b=0.37 (95% CI 1.3-7.6); p=0.006].

In summary, HCV coinfection is associated with increased apoptosis of T lymphocytes in HIV+ patients, which could explain a more rapid CD4 decline and an impaired CD4 recovery following initiation of HAART in coinfected individuals.

02/24/06

References

1. J Nattermann and others. Effects of cytokine gene polymorphisms on treatment of acute hepatitis C infection in HIV-infected patients. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006. Denver, CO [Abstract 83].

2. A Kim and others. Virus-specific T-cell responses and loss of spontaneous control of HCV in HIV+ individuals. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 84].

3. L Valerio and others. Earlier versus later ART initiation in HIV/HCV coinfected patients: a model-based analysis. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 891].

4. L Capa and others. Effect of HIV coinfection and treatment with pegylated interferon + ribavirin in hepatitis C virus-specific immune responses. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 850].

5. M Nunez and others. Coinfection with hepatitis C virus increases lymphocyte apoptosis in HIV-infected patients. 13th Conference on Retroviruses and Opportunistic Infections. 5-8 February 2006, Denver, CO [Abstract 847].