IMMUNOLOGY OF HIV INFECTIONS part 17

Innate immunity has been mostly neglected in favor of HIV-specific immunity in HIV vaccine studies. CCL3 production should be considered a correlate  of protective immunity. A desired response would be sufficient production of CCL3 at the site of HIV and vaccine encounter. It is imperative to delineate the precise functions of CCL3 in the immune response to HIV, aside from its noncytolytic inhibitory effect on HIV, as the ability of CCL3 to drive the development of adaptive immunity might be the crucial factor in overall protection. Many important questions arise, given the findings outlined here. How should HIV vaccines be designed? How can people who would be poor responders to vaccines (deficient CCL3 producers) be identified? How can the genetically encoded loss of function be overcome, and how can molecules be identified  that can compensate for this? Innate immunity must become a more integral component of studies of HIV vaccines, as understanding the interaction between innate and adaptive immunity may hold the key to understanding what constitutes protective immunity to HIV. Studies of uninfected infants born to HIV-infected mothers offer a unique human experimental model for extending the understanding of such phenomena.

IMMUNOLOGY OF HIV INFECTIONS part 16

Turning to their use as vaccine candidates, Tiemessen and colleagues (2007) suggest that, if CCL3 is a crucial molecule in protection against HIV by virtue of its adjuvant ability, it may be useful as a vaccine adjuvant. In this manner, one does not have to rely on the host's ability to produce it (production may be deficient in certain population)

IMMUNOLOGY OF HIV INFECTIONS part 15

However, this observation does not completely explain why some babies are infected with HIV and others are not. In a landmark study, Gonzalez and colleagues (2005) showed that segmental duplication occured in the gene CCL3L1-like chemokine. CCL3L1 as well as CCL3 are ligands for CCR5 and are associate with lower susceptibility to HIV. Moreover, a study of maternal-infant HIV transmission has shown that a phenotype of deficient mitogen-induced CCL3 production is associated with a greater risk of HIV infection during labor and delivery. Thus the maternal-infant model has demonstrated that the protein encoded for one or both of the functional genes (CCL3 or CCL3L1) is involved, suggesting that the abundance of this protein may be important in HIV-protective immunity. Functional capacity, not just gene copies (four or more in some cases) of these proteins, is important. This suggests that the "susceptibility phenotype" lives at the level of induction of gene expression of CCL3 and CCL3L1, resulting in qualitative differences in protein production.

IMMUNOLOGY OF HIV INFECTIONS part 14

The initially unexpected finding of HIV-specific CD4 and CD8 T-cell responses among uninfected sex workers paved the way to the fact that natural protective immunity may exist. It has been difficult to repeat these studies in infants because of small blood volumes. Nevertheless, some studies, using IL-2 production as a marker following stimulation with envelope peptides, have shown that none of the children with apparent HIV-specific T-cell response developed HIV infections despite exposure to HIV through breast feeding.

IMMUNOLOGY OF HIV INFECTIONS part 13

Although the story of the African sex workers who seem to be immune to HIV infection has captured the imagination of many researchers, there is another model of natural immunity that needs examination in more detail. Most babies born to HIV-infected mothers also escape infection even after potential intrauterine exposure and, more important, exposure to virus-containing blood and secretions during labor and delivery. Finally, breast-fed infants ingest hundreds of liters of virus-infected breast milk. Many factors such as CD4 cell counts and viral load in the secretions must be considered. One should add that, like the sex worker model, it is a "real"-world situation of viral encounter opening a window to the "in vivo" infection moment. Although interesting, there are, however, several drawbacks to the model; notably, the newborn is immunologically immature compared with later in life. However, their capacity to produce CC cytokines is greater compared with their mothers whether she is HIV infected or not. This is consistent with the expected skewing toward a stronger innate response rather than the adaptive response.

IMMUNOLOGY OF HIV INFECTIONS part 12

DC interaction with HIV is relevant to the pathogenesis of AIDS because they are present in the mucosa and skin of humans and are believed to be the first HIV-1 targets following sexual transmission of the virus. Both myeloid DC and plasmacytoid DC possess the receptors for HIV entry ; that is, CD4, CXR4, and CCR5 can be infected but with a lower efficacy  than CD4 cells or macrophages. The long-term result of this infection is that DC remains a reservoir for the production and persistence of the HIV-1 virus, and the virus induces several functional impairments and variations in the DC populations. Thus, the number of both myeloid DC (MDC) and peripheral  DC (PDC) are significantly decreased in HIV-positive progressors, while remaining unaltered in HIV-positive long-term nonprogression. The destruction of these cells may be a consequence of direct lytic infection or as targets for specific CTL or through a block in DC development from peripheral CD34 stem cells. More recent evidence supports the notion that both midi and pad show impaired functional capacity in HIV-positive patients. Since both DC subsets participate in the initiation of innate and adaptive immune responses, infection, depletion, and dysfunction of DCs may contribute to the immunesuppression seen in HIV disease. Therefore, DCs play a dual role in HIV infection: they trigger both innate and adaptic immune responses to control the infection, but they also represent a viral reservoir for infection of permissive CD4 T cells.

IMMUNOLOGY OF HIV INFECTIONS part 11

One of the key cells in the immune surveillance system is the native DC, which is well equipped for activation of both the innate and adaptive immune response. It has been demonstrated that some DC-tropic viruses such as influenza virus leave DC function intact while other viruses such as HIV and cytomegalovirus have evolved  strategies to impair DC functions, thereby enhancing the virus's ability to persist and escape immune surveillance.