HIV-specific immune responses key to speed of disease progression

HIV-specific immune responses act to slow HIV disease progression, according to articles published in recent editions of the Journals of Infectious Diseases, Journal of Immunology, and The Lancet. The studies could have important implications for future HIV vaccine research.

Many of the experimental HIV vaccines currently in development - both preventive and therapeutic - are designed to induce T-cell responses targeting the virus (also described as HIV-specific cell-mediated immunity or CMI). However, it remains highly controversial as to whether such responses can offer a benefit in terms of preventing infection, slowing post-infection disease progression or reducing reliance on antiretroviral drugs. Some studies have suggested that the magnitude of the HIV-specific T-cell response is inversely correlated with viral load, while others have found no - or even the opposite - correlation. Adding to the confusion, these divergent outcomes are often associated with the use of different methods for measuring HIV-specific T-cells. Several newly published studies suggest that HIV-specific CMI may have a salutary effect on the rate of disease progression in HIV-infected individuals, and offer potential explanations for the seemingly contradictory results that have been reported previously.

An article published in the April 1^st edition of the Journal of Infectious Diseases reports that HIV-specific T-cell responses play a role in slowing disease progression. A group of researchers from the Institute of Microbiology in Zurich evaluated the magnitude of HIV-specific CD4 and CD8 T-cell responses in a cohort of 28 untreated individuals with CD4 T-cell counts above 250 cells/mm³. This group of individuals has been followed for two to 17 years as part of the Swiss HIV Cohort study. HIV-specific T-cell responses were quantified using an ELISA spot assay that captures cells based on their ability to produce the cytokine interferon-gamma after stimulation with HIV antigens. For CD8 T-cells, responses targeting HIV antigens from all viral proteins were evaluated, but for CD4 T-cells, only responses targeting the viral p24 protein were measured. The rate of disease progression in the untreated study participants was assessed based on the surrogate markers of CD4 T-cell counts and viral loads, which were used to calculate the yearly rate of CD4 T-cell count decline in each individual.

The researchers uncovered a strong statistical trend associating greater HIV-specific CD8 T-cell responses with slower declines in CD4 T-cell counts (p=0.054), and a statistically significant association between higher HIV-specific CD4 T-cell responses and slower declines in CD4 T-cell counts (p=0.003). However, neither type of response was correlated with viral load levels. To try and ascertain whether the HIV-specific T-cell responses were truly playing a causative role in slowing disease progression (as opposed to simply appearing as a consequence of lower viral load and slower progression), the researchers compared the responses seen in the untreated individuals with those measured in ten HAART-treated study participants with comparable viral loads and total CD4 and CD8 T-cell counts. Frequencies of HIV-specific CD4 and CD8 T-cells were statistically significantly higher in the untreated individuals, leading the researchers to conclude that “this lends support to the speculation that stronger HIV-specific cellular immunity in untreated patients is at least partly responsible for this clinical phenotype (i.e. slower progression) and that it is not merely a consequence of lower viral replication.” However, they also acknowledge the possibility that the potentially drug-resistant (and perhaps less-fit) virus that exists in HAART-treated individuals with detectable viral loads “may induce fewer specific immune responses that are of lesser magnitude”.

Two additional studies also report that HIV-specific CMI plays a role in controlling viral replication, and add to a growing body of data suggesting that quantifying HIV-specific T-cells based solely on their ability to produce interferon-gamma may not provide a complete picture of the functionality of these cells. These data could go some way toward explaining why it has been difficult to establish correlations between HIV-specific T-cell responses and control of viral load.

The first study, published in the March 1^st issue of the Journal of Immunology by investigators from the University of Colorado, reports that production of interleukin-2 (IL-2) is an important function of HIV-specific CD4 T-cells that is absent or reduced in individuals with progressing disease, despite the fact HIV-specific CD4 T-cells producing interferon-gamma can typically still be detected. The article also reveals that the ability to produce IL-2 is linked to the maturation state of the HIV-specific CD4 T-cells, a finding that echoes results seen in studies of CD4 T-cell responses using mouse models of viral infection.

Maturation refers to changes that T-cells (both CD4 and CD8) undergo after becoming activated by a first encounter with an infectious agent. During a typical immune response, naïve T-cells specific for the infectious agent become activated in the lymph nodes, undergo multiple divisions and migrate to sites in the body where the agent is replicating in order to control or clear the infection. Upon resolution of the infection, many of these activated naïve (or "primary effector") T-cells die, but some survive as memory T-cells. Should these memory T-cells (christened "central memory T-cells" by immunologists) encounter the same infectious agent again, a new wave of T-cell activation and division ensues and these activated memory (now dubbed "memory effector" or "secondary effector") cells once again attempt to control or clear the infection (if successful, these memory effector cells return to a de-activated resting state and are once again categorized as central memory T-cells). Importantly, memory T-cells respond more rapidly and efficiently than naïve T-cells, suggesting that both central memory T-cells - and the memory effector T-cells they can generate - are likely to be important in controlling pathogens that remain in the body for life. Certain cell surface markers (such as CD45RA, CD45RO and CCR7) can be used to roughly gauge the maturation state of a T-cell, although there is still some debate as to precisely which suite of markers equates with each stage of maturation.

The Colorado study found that the number of HIV-specific CD4 T-cells producing IL-2 and possessing cell surface markers associated with central memory T-cells correlated inversely with viral load (the higher the frequency of these responses, the lower the viral load). This finding appears to confirm previous studies published by Mark Boaz and colleagues from King’s College in London and Alexandre Harari and colleagues from the University of Lausanne in Switzerland, which also reported inverse correlations between the numbers of IL-2-producing HIV-specific CD4 T-cells and viral load levels.

A second recent study suggests that there may also be a link between the maturation state of HIV-specific CD8 T-cells and control of viral load, a link which is not evident if production of interferon-gamma is used as the sole criteria for measuring the HIV-specific CD8 T-cell response. A research letter published in the March 13^th issue of The Lancet reports that the maturation state of HIV-specific CD8 T-cells correlates with control of viral load after interruption of HAART. CD8 T-cells mature in a manner similar to CD4 T-cells (described above). This study evaluated the maturation state of HIV-specific CD8 T-cells (based on cell surface markers) in individuals with acute HIV infection participating in a study of HAART treatment followed by structured treatment interruptions (STIs). Although the study only included a small number of individuals, the research team from Harvard Medical School uncovered a statistically significant inverse correlation between the percentage of fully matured (or differentiated) “memory effector” HIV-specific CD8 T-cells and viral load levels during STI.

To try and understand whether these fully differentiated CD8 T-cells appeared simply as a consequence of low viral loads, the researchers also studied seven individuals who did not display any evidence of control of viral load except when on HAART. These individuals all possessed very low percentages of fully differentiated HIV-specific CD8 T-cells, even when viral load was suppressed by HAART. A comparison of the percentage of fully differentiated HIV-specific CD8 T-cells in the six study participants who were off HAART but who controlled viral load and five individuals who did not control virus replication in the absence of HAART revealed a statistically significant difference (p=0.0043).

The analysis was next extended to six long-term non-progressors (LTNPs) who have maintained viral loads less than 2,000 and CD4 T-cell counts over 500 cells/mm³ for three to 20 years. Similar to the acutely infected individuals who showed periods of control of viral load after STI, these LTNPs showed high percentages of these fully differentiated HIV-specific CD8 T-cells. The researchers conclude by noting that “there is a strong association between control of viral replication and the presence of preserved virus-specific CD4 T-cell function in both acute-STI patients and non-progressors, suggesting that maturation of virus-specific CD8 T-cells might be linked to the preservation of HIV-specific CD4 T-cell function. How the extent of the fully mature HIV-specific CD8 T-cell repertoire is linked to control of viral replication, and how full maturation relates to CD4 and CD8 T-cell proliferative capacity needs to be studied in more immunological detail and in larger cohorts.” The investigators also stress that the cause-and-effect relationship between the presence of IL-2-producing “central memory” HIV-specific CD4 T-cell responses and lower viral loads remains to be definitively determined.

Taken together, these studies infer that HIV-specific CMI acts to slow disease progression and - if particular functional and maturation markers are taken into account - the magnitude of HIV-specific CMI can be correlated with control of viral load. The data offers hope that vaccine strategies aimed at inducing HIV-specific memory CD4 and CD8 T-cells may ultimately be able to provide benefit in terms of enhancing immune control of viral replication and thereby delaying disease progression in vaccinated individuals who subsequently become HIV-infected. The findings may also be encouraging for researchers attempting to induce new HIV-specific memory CD4 and CD8 T-cell responses in infected individuals on HAART through the use of therapeutic vaccination.