he human immunodeficiency virus type 1 (HIV-1) is presently one of the major human pathogens for which no prophylactic vaccine is available. The definition of the mechanisms that may protect against HIV-1 infection has been a daunting task but recent experimental studies with animals (1, 2) and with HIV-1-exposed, persistently seronegative (HEPS) individuals, who remained uninfected despite years of exposure, have provided new insights that may be important for the development of an HIV-1 vaccine.

In recent years, the phenomenon of natural resistance has been evaluated in several groups worldwide. In Europe, HIV-1 specific cytotoxic T lymphocyte (CTL) activity was detected in uninfected partners of HIV infected individuals (3). Similar occurrences have been observed in several other groups(4, 5).

HIV-1 specific IgA has been detected in HEPS individuals from both Europe and Africa (6, 7). We have shown that mucosal IgA was able to neutralize or inhibit mucosal transcytosis of primary clade A and B or A-D and A-E isolates respectively in vitro, suggesting a functional role in vivo for these antibodies (8, 9).

A more clade-restricted pattern of neutralization was found in partners of clade B-infected individuals. What factor(s) could explain the difference in the ability to neutralize different clades of HIV-1?

The women in the cohort of female sex workers most likely have been exposed to many clades and variants of HIV as well as to individuals with different viral loads. However, they still were not infected for many years, despite the high and repeated exposure to the virus. It is likely that individuals in this cohort have antibody profiles that provide them with a broader HIV-1 neutralization pattern than the profiles of seronegative partners of HIV-1 infected individuals, who have a more restricted exposure to HIV. Additionally, a few of these women have seroconverted after being away from their work, or after reducing the number of clients. These changes resulted in a drop of the HIV-specific IgA titers, supporting the idea that a high and continuous exposure to the virus is necessary to maintain the specific mucosal immune responses.

How do you explain the fact that IgA purified from HIV-1 infected subjects also mediate cross-clade neutralization? Why are these individuals not protected against HIV-1 infection?

It is true that broadly and cross-clade neutralizing antibodies can be found in HIV-infected individuals, however they are not protective. There are one or more possible explanations for this, for example: a) the antibodies were not present in these individuals at the time when they became infected, b) the antibody amounts were simply below the protective level, c) the infecting HIV-type did not expose the proper neutralizing epitopes, and d) cell-mediated immune responses such as CTLs are necessary to provide full protection. These several possibilities will have to be addressed if we want to understand the true nature of a fully protective immunity. It seems likely that at both humoral and cell-mediated immunity, as shown for example with lymphocytic choriomeningitis virus in mice, will have to be active to provide full protection.

How protective is IgA against HIV-1 infection?

An HIV-1 gp41 epitope recognized by IgA from exposed seronegative individuals has been identified and shown to differ from the epitopes recognized by HIV-1 positive individuals (10). Immunizations of mice with this epitope have been performed alone or in combination with an HIV-1 gp160 envelope DNA vaccine. The results indicated that the animals developed a broad HIV-1 gp41 specific humoral and cellular immunity. To find out if the developed mucosal IgA is indeed protective, a combinatorial library approach will be used to obtain human and murine monoclonal IgA antibodies against these epitopes. The functionality and neutralizing properties of these antibodies will then be tested, for example in passive immunotherapy studies as has been done with HIV-specific IgG.

What is the perspective of developing an HIV-1 vaccine based on this finding? In this case, what kind of mechanism would you consider to trigger the immune response against HIV-1?

In order to induce a response similar to the one seen in HEPS subjects, a prime-boost immunization with a DNA vaccine expressing the HIV-1 gp160 envelope antigen followed by a gp41 booster was performed (11). The immunization resulted in a broad IgG and IgA recognition of conserved epitopes, both systemically and in mucosal surfaces, and a long-lasting B- and T-cell memory. Our main aim was to trigger and activate mucosal immunity based on our findings that there is a correlation between IgA in mucosal samples collected from HEPS individuals in Europe and Africa and their resistance to HIV-1 infection. However, the presence of HIV-1 specific IgA may not be the only requirement for resistance to HIV-1 infection. A combination of different immune mechanisms together with adaptive and innate factors may be necessary to provide full protection against HIV-1. Lacking one or several of these factors may be enough to weaken a protective immunity.

Conclusion

Studies on HEPS individuals have suggested that mucosal immunity in HIV infection is an important factor to be considered when designing the prophylactic vaccine urgently needed to control the spread of the HIV pandemic. This vaccine should evoke systemic, broadly neutralizing antibody responses in the mucosa, as well as HIV-1-specific CTLs to functionally relevant epitopes.

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