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Immune Mechanisms of Viral Control in HIV-1 Subtype C Infection

Research Summary

Thumbi Ndung'u is interested in understanding antiviral immune mechanisms and viral adaptation in HIV-1 subtype C infection as a pathway to vaccine development.

The primary focus of my laboratory is to understand immune responses associated with human immunodeficiency virus type 1 (HIV-1) control as a pathway to rational vaccine design and development. We study HIV-1–infected persons, particularly in the high-burden country of South Africa, where the overwhelming majority of infections are caused by HIV-1 subtype C, the predominant strain in the world. HIV-infected people who are antiretroviral-therapy-naive display heterogeneity in their ability to control the virus and in their disease progression profile. There is overwhelming evidence that immune mechanisms are at least partially responsible for differences in viral control and rate of disease progression, and we hope to identify the specific mechanisms involved. So far, we have generated some evidence that a complex interplay between antiviral immune responses, host genetics, and virus genetics is involved in determining the clinical outcome of exposure or infection with HIV-1 subtype C viruses.

The most significant genetic correlate of HIV control is human leukocyte antigen (HLA) class I type. HLA class I molecules are involved in the presentation of segments of the virus (known as epitopes) to cells of the immune system known as cytotoxic T lymphocytes (CTLs). We have identified the main viral protein targets of CTLs in chronic HIV-1 subtype C infection and defined some CTL responses that are more effective than others in suppressing virus replication. We have also shown that during the early phases of HIV-1 infection, before full seroconversion has been achieved, the body is unable to mount detectable immune responses to some viral epitopes despite the presence of wild-type virus sequences that should induce an immune response, based on patterns of responses seen in chronically infected persons. We are interested in extending this work further to identify the most effective T lymphocytes in people with acute HIV-1 subtype C infection, to understand the biological characteristics that distinguish immunosuppressive CTLs from noneffective ones, and to understand why certain immune responses are not generated. Recently, we demonstrated that genetic polymorphisms in the immunoregulatory cytokine interleukin 10 (IL-10) may affect the quality of immune responses, and we are keen to explore the underlying mechanisms further.

We have also been studying how the HIV-1 subtype C virus adapts to cytotoxic T cell immune pressure or escapes immune recognition, and the consequences of this immune-driven sequence variation for the virus and clinical disease outcome. Using a population of over 400 chronically infected people, we showed that recombinant viruses constructed using patient-derived Gag-protease proteins can differ widely in their in vitro replicative fitness. The replication capacities of these viruses correlated positively with viral load and negatively with CD4 T cell count, suggesting that viral fitness can be a determinant of clinical outcome. We also found that Gag-protease-driven viral fitness varies significantly across different HLA-B class I alleles but not HLA-A, HLA-C, or HLA class II alleles. Some clinically beneficial (protective) HLA class I alleles were associated with significantly lower viral replication capacities, and individuals with the least fit viruses more frequently possessed protective HLA class I alleles. Furthermore, our work demonstrated that immune-driven mutations in p24 Gag (nonconsensus mutations) more frequently reduced viral replication capacity, whereas mutations in Gag p17 increased virus replication capacity. Therefore, our work so far suggests that HLA-B alleles (but not HLA-A, HLA-C, or class II alleles) are exerting immune pressure that drives the virus to a less-fit state, and that this may be clinically beneficial. In the future, we hope to gain a more in-depth understanding of anti-HIV immune responses, immune escape pathways, and functional consequences for the virus from the earliest stages of infection. We hope that through these studies we can define the precise balance of immune responses and viral fitness required to achieve and maintain effective viral control.

We have also studied the role of intrinsic immunity (host-restriction factors) in HIV control. Intrinsic immune factors are intracellular proteins that are thought to comprise part of the ancient innate immune mechanisms against viruses. Our laboratory is interested in understanding whether these molecules have any antiviral activity and effectiveness in vivo. So far, we have shown an association between the expression levels of human TRIM5α and reduced susceptibility to HIV-1 infection in a well-characterized clinical cohort, although a direct causal relationship is yet to be proven. We also demonstrated that higher expression of a related host-restriction factor, TRIM22, is associated with modest viral control during primary HIV-1 infection, and that knockdown of this factor in vitro can enhance virus replication and release. We hope to further explore how these factors are regulated and how the virus may escape from or counter these immune mechanisms. We have also done exploratory work to gain understanding of other host-virus interplay interactions that may affect the clinical course of HIV-1 infection.

The philosophical underpinning of our work is that, considering the difficulties so far encountered in developing an effective HIV vaccine, we should vigorously pursue promising avenues of vaccine design while exploring unconventional ideas that have not previously been widely studied, especially in human populations most severely affected by HIV/AIDS. We also have a special interest in developing a critical mass and building capacity for biomedical research in Africa.

Grants from the National Institutes of Health, the South African AIDS Vaccine Initiative, the South African Department of Science and Technology through the National Research Foundation, the Bill and Melinda Gates Foundation, and the Hasso Plattner Foundation provided partial support for these projects.

As of January 17, 2012

Scientist Profile

International Early Career Scientist
University of KwaZulu-Natal
Immunology, Virology