 |
Immune Control in Chronic Human Viral Infections
Summary: Bruce Walker seeks to determine how the immune system controls chronic viral infections and to augment antiviral immunity for therapeutic benefit.
Despite dramatic clinical effects resulting from the advent of highly active antiviral therapy (HAART) for the treatment of HIV-1 infection, it is increasingly clear that viral eradication will not be easily or, more likely ever, achieved. Some persons, however, have now been infected with HIV for more than 20 years without developing progressive disease, even though they have never been treated with antiviral drugs. These persons seem to have achieved with HIV-1 what is achieved with other chronic viral infections such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV)—viral containment rather than eradication. Our goal is to understand the immune control of chronic viral infections and to use this information to develop interventions to induce immunologic control in persons with otherwise progressive infections. In our research we use human clinical specimens and focus on the rapid translation of research advances at the bench to clinically relevant interventions at the bedside. Our work focuses entirely on human diseases, for the most part concentrating on well-defined cohorts in the United States and in KwaZulu-Natal Province, South Africa.
Correlates of Immune Protection in HIV Infection
Our laboratory identified HIV-1–specific cytotoxic T lymphocyte (CTL) responses in infected persons, detected strong virus-specific T helper cell responses in persons whose viremia is controlled without treatment, and demonstrated that early treatment of acute infection leads to increased immunity and the transient ability to control viremia in the majority of infected persons. In our attempts to understand immune control of HIV, we are focusing on a unique cohort of more than 60 infected persons who have viral loads at or below the limits of detection by the most sensitive RNA detection assays (>50 RNA copies/ml plasma), despite never having been treated with antiviral drug therapy. We term these persons "elite controllers." We are studying the viral, host genetic, and immunologic factors associated with this control.
Evolution of Immune Responses in Acute HIV Infection
Our research studies are very much influenced by our experiences as clinicians caring for patients. One such area is the acute stage of HIV infection. Over the past 5 years, we have identified more than 200 persons with acute infection, usually presenting with a flu-like syndrome. We recently demonstrated that the specificity of the CTL response in chronic HIV infection differs from that in acute infection, and that some CTL responses that are dominant in chronic infection are not generated until well after the initial decline in viremia in acute infection. Through a unique cohort of persons with both treated and untreated acute HIV infection, we are assessing the earliest targets of the immune response in human viral infection. Among the hypotheses to be tested are (1) high-affinity and high-avidity CTL responses are generated earliest against HIV, (2) loss of these initial responses occurs at the time of highest viral load, with resultant evolution of clonal responses that are less effective at controlling viremia, and (3) immunodominance is influenced by differing kinetics of class I antigen processing and presentation.
Correlates of Loss of Immune Control in HIV Infection
Most studies to date have focused on the correlates of immune protection in HIV infection. Studies of treatment interruption in acute HIV infection now offer the opportunity to determine the correlates of loss of control of viremia. In studies conducted thus far, we have observed persons who control an initial burst of viral replication, often to below the limits of detection, but who experience viral breakthrough up to 18 months later. We are testing whether immune escape from effective CTL responses results in viral breakthrough. These studies will also allow us to determine what host genetic factors are associated with prolonged immune control of infection. More recently we have identified viral breakthrough in a person with well-controlled viremia in the absence of antiviral therapy, which was due to superinfection by a closely related strain of HIV. Despite broadly directed and high-magnitude CTL responses, the new strain replicated robustly upon superinfection. This case provides important insights into the challenge of developing broadly cross-reactive HIV vaccines. We are currently investigating whether functional defects in CD8+ T cells underlie the lack of immune control in the chronic phase of infection, and the extent to which these defects may be linked to abnormal CD4+ T cell function.
Augmentation of Effective Immunity in HIV Infection
The existence of persons who are able to control viremia spontaneously, along with the demonstration that effective immune responses against HIV can be augmented by early treatment of acute infection, provides a rationale for attempts to increase immunity to HIV in infected persons. In a comprehensive immunotherapy program at Massachusetts General Hospital, we are testing the hypothesis that early treatment of acute infection leads to augmentation of T helper cell responses, but the magnitude and breadth of CTL responses is insufficient to allow for effective control. An alternative hypothesis is that in chronic infection, lack of T helper cell responses to HIV limits the ability to induce new responses, but HAART leads to induction of new naïve cells, which can then be rendered antigen-specific through therapeutic immunization or the use of autologous dendritic cells pulsed with immunogenic peptides. Our early efforts have been focused on supervised treatment interruption to expose the immune system to an immunogenic dose of virus. We are also testing peptide-pulsed dendritic cells as well as vaccine candidates for therapeutic benefit in persons with chronic progressive infection.
The Relationship Between Immune Selection Pressure and Viral Evolution
It has been known for some time that partially effective antiretroviral drug therapy is associated with the development of key mutations that render the virus able to evade these medications. HIV is also under partial immune selection pressure, in that the virus is inhibited but not fully contained in most infected persons. Our initial studies in maternal-infant transmission events demonstrated the evolution and transmission of stable CTL escape variants. These immune escape variants persist even in the absence of the immune pressure that selected them, suggesting that these will accumulate over time as the epidemic progresses. A critical aspect of our research effort is to determine the influence of immune selection pressure on viral evolution by examining viruses that are under different selection pressure. To this end we are conducting a large-scale analysis of immune responses to HIV in a cohort of more than 1,000 HIV-infected persons of Zulu-Xhosa descent in KwaZulu-Natal Province, South Africa. These studies involve comprehensive analysis of immune responses to all expressed HIV proteins, high-resolution HLA typing, and viral sequence analysis. The studies thus far show that HLA-B alleles are the dominant alleles that influence viral load in HIV-infected persons, and will allow us to define those responses that are most associated with an antiviral effect.
This work has been supported by the Doris Duke Charitable Foundation and the National Institute of Allergy and Infectious Diseases.
Last updated: February 6, 2008
|
|
|
|
