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Immunology and treatment interruption data presented at the 42nd ICAAC

13 November 2002. Related: Conference reports, Treatment strategies, .

Mark Dybul MD, National Institutes of Health (NIH) for HIVandhepatitis.com

All references are to the Programme and Abstracts of the 42nd ICAAC.

The immunological discussions regarding HIV at the 42nd ICAAC in San Diego focused largely on mechanisms of immune control of HIV, potential mechanisms to enhance immune control of HIV, and the possibility of interrupting HAART in certain patients who may have relatively intact immune systems as determined by CD4+ T cell counts.

Immunological control of HIV

The biggest news regarding HIV during the conference was David Ho’s presentation describing his lab’s recently published work identifying alpha-defensins -1, -2 and -3 as the elusive CD8 antiviral factor (CAF), soluble factors produced by CD8+ T cells that are responsible for the suppression of HIV in vitro that cannot be attributed to beta-chemokines (MIP 1- alpha and beta and RANTES). (Symposium 139 (H), abstract 1192)

Alpha-defensins are commonly used by the immune system to suppress the activity of extra-cellular bacteria. Levy’s group was the first to describe the existence of CAF in 1986, and in 1995 Gallo’s laboratory identified the beta-chemokines as the major soluble suppressor factor for HIV species that utilise the chemokine coreceptor CCR5, the coreceptor utilised by most viral strains until late in disease.

However, the beta-chemokines had no effect against HIV species that utilise the chemokine receptor CXCR4, and several groups have reported that beta-chemokines do not account for all of the CAF activity of CD8+ T cells against CCR5-utilizing HIV.

In this context, Ho presented his lab’s work identifying the alpha-defensins as the allusive CAF that is not beta-chemokine. Ho studied the CD8+ T cell CAF of three patients in the Aaron Diamond cohort of long term non-progressors (LTNP) who exhibited strong CAF activity in vitro. They then evaluated the supernatants of activated CD8+ T cells from these three patients, four progressors and 15 HIV-uninfected controls by protein chip analysis ; this analysis allows for the identification of small, highly charged proteins that could not be studied easily by technology that was previously available.

Upon identifying alpha-defensins by protein chip analysis, Ho described the experiments whereby antibodies to the alpha-defensins nearly eliminated the ability of CD8+ T cells obtained from LTNPs to suppress CXCR4-utilising HIV in vitro. In addition, antibodies to alpha-defensins, when combined with antibodies to the beta-chemokines, nearly eliminated the ability of CD8+ T cells obtained from LTNPs HIV-infected individuals to suppress CCR5-utilising HIV.

Ho then described experiments in which the alpha-defensins were added in vitro to try to block the ability of six isolates of CXCR4 and CCR5- utilising HIV, and while the results were less impressive, Ho commented that this was likely due to the alpha-defensins currently available not being highly purified. In these experiments, antibodies to the alpha-defensins eliminated the suppressive activity; as was seen in the previous experiments.

Ho noted that the clinical applicability of his findings is unclear; this may be the case because of the difficulty of producing these proteins in a highly purified form, and the potential difficulty of giving the proteins in a high enough concentration to have clinical effect.

In addition, there may be other CAF-related factors that remain to be identified, particularly CAF that may be identified in patients with chronic HIV infection. However, from the data presented it seems the alpha-defensins may play a significant role in suppressing HIV replication in vivo.

Enhancing immune control of HIV

DC-SIGN – gp120 interactions

Although not a mechanism of control of HIV infection in vivo, Kooyk presented her lab’s work elucidating the early events in HIV infection with the hope that therapeutic strategies could be developed to prevent certain means by which HIV seems to co-opt the immune system (abstract 1193). Kooyk et al have previously demonstrated that DC-SIGN, a C-type lectin found on dendritic cells (DC), plays a key role in binding HIV and may therefore be responsible for transporting HIV on DC from the mucosa (vaginal or rectal) to the lymph nodes to disseminate infection. However, DC-SIGN also participates in the regulation of interactions between T cells and DC through ICAM-3, and this interaction is important for inducing an immune response.

Kooyk reported that DC-SIGN has different binding sites for gp120 of HIV and ICAM-3. Therefore, it may be possible to design specific therapies to block the DC-SIGN – gp120 interaction without adversely affecting the beneficial immunologic effects of DC-SIGN – ICAM-3 interactions. In this regard, Kooyk presented data on the identification of antibodies against gp120 that block its interactions with DC-SIGN; this could be a novel vaccine strategy based on a better understanding of HIV immunopathogenesis.

Effects of HAART on immune responses

Smith et al (abstract H-1743) presented their work evaluating thymus size and CD4+ T cell reconstitution following HAART. The authors have previously demonstrated a relationship between a larger thymus size and recovery of naive CD4+ T cells following short term HAART.

In this study, 23 patients underwent thymus CT scans at one and three years of HAART. In 12 patients there was a decrease in size, in nine there was no change, and in two the size increased. However, patients with abundant thymic tissue (five patients) at year three had significantly more naive CD4+ T cells (240) than those with minimal thymic tissue (105, P = 0.007). In addition, 86% of patients had a decrease in IL-7 levels from year one to year three; IL-7 has been associated with T cell depletion in HIV disease.

The authors conclude that IL-7 levels and the thymus appear to be important for T cell restoration in patients receiving HAART.

Forcina et al (abstract H-1747) reported on the positive effects of HAART on the ability of CD4+ and CD8+ T cells to produce the beta-chemokines MIP-1 alpha and beta and RANTES (see above). Six HAART naive, six complete HAART responders and six patients failing HAART were evaluated by stimulating cells with PHA in vitro.

The patients receiving an effective HAART regimen produced a higher level of all three chemokines by both CD4+ and CD8+ T cells compared to HAART-naive patients and those failing HAART, and the levels approximated those of HIV-negative donors. IL-15 enhanced the production of only MIP-1- beta in the drug naive and failing patients, while it increased levels of all three chemokines in patients receiving effective HAART and in healthy donors.

These data lend further support to the potential role of IL-15 as an immunotherapeutic agent, particularly in patients treated effectively with HAART.

Loss of CD4+ T cells during treatment interruptions

There is a growing interest in the clinical safety of discontinuing HAART in patients with < 50 copies/ml of plasma HIV RNA and relatively high CD4+ T cell counts to spare potential toxicity of the drugs and to improve the quality of life of patients.

Seminari (abstract H-1745) presented results from 62 patients with CD4+ T cell counts > 300 and viral load < 50 c/ml in patients who had received a PI-containing regimen for > 6 months. These patients received an intermittent regimen of one month on HAART followed by one month off HAART for six-12 months (76% had reached 12 months). Patients were required to resume therapy if the CD4+ T cell count went below 200; five of the 62 patients met this criterion and all had a nadir CD4+ T cell count < 50 prior to HAART.

Although 12 patients with the same nadir CD4 count did not have drops to < 50 cells, there was a significant risk of reaching the CD4 endpoint for patients with that nadir CD4 count (P=0.005).

These data suggest that patients with low nadir CD4 counts may not be good candidates for treatment discontinuation or intermittent therapy approaches.

References:

All references are to the Program and Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd ICAAC). September 27-30, 2002. San Diego, California.

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