Development of an effective HIV vaccine is a major and important focus of basic AIDS research. In this regard, the recent commentary by Ron Desrosier in Nature Medicine was very timely . Certainly, more fundamental studies must be conducted if the derivation of a successful vaccine is to be achieved. What Desrosier did not consider, however, is the potential role of innate immunity in increasing the immunologic response to HIV. Most attention thus far has been given to adaptive immunity; the scientific community should turn to studies of the innate immune response as a potential means of improving vaccination results . Desrosier describes reports on SIV infection in which adaptive immune responses could not explain protection or lack of protection induced by the experimental vaccines. Innate immunity may have been the major determinant in these studies.
The innate immune system is composed of a large number of cellular and soluble components, including most of the cytokines, chemokines, complement, and lectin-binding proteins. By a system of pattern recognition, these innate immune system participants can recognize many different potential pathogens and respond quickly to them. Subsequently, the production of cytokines by the stimulated innate immune system can elicit both innate and adaptive cellular responses to the invading organism. In the case of HIV, innate immunity has the advantage of not being virus specific, but responding quickly to a wide variety of HIV isolates. Moreover, resistance to this immune activity has not been described.
Innate immunity is particularly valuable at local mucosal sites such as the vaginal and anal canals where a rapid response (minutes to days) is needed and can be mediated by soluble and cellular components (e.g., NK cells, NKT, and γδ T cells). Such a quick response provides time for the more specialized adaptive immune activities to develop. Thus this early recognition of a pathogen can greatly determine the outcome of the infection. Toward this objective, vaccine studies with adjuvants can target innate molecules such as TLR-4 and TLR-9 on dendritic cells (DC) [3,4] and DCs can be used in vaccine approaches . A beneficial role of γδ T cells elicited by a vaccine for protection against SIV challenge has also been suggested [6,7].
Recent work in innate immunity has emphasized the potential roles of soluble factors as well as cellular components such as plasmacytoid dendritic cells (PDC), the major producer of interferon-α, and CD8 T-cell noncytotoxic antiviral responses (CNAR) in preventing HIV infection and pathogenesis . High levels of PDC are found in long-term survivors of HIV infection and are associated with low viral loads in acute infection . In addition, they are present in rare untreated infected individuals who have very low CD4 cell numbers (< 150 cells/μl) but no clinical symptoms . The PDC, via interferon production, appear to protect against disease by direct antiviral activity and, importantly, by eliciting innate and adaptive cellular immune responses . In this regard, an increase in PDC number via co-administration of G-CSF and Flt3 ligand or thrombopoietin [9,10] could be helpful in an HIV vaccine strategy.
CNAR suppresses the replication of a wide range of lentiviruses as well as other retroviruses (e.g., simian, human, cat, mouse) by acting on viral transcription via the long terminal repeat (LTR) [2,11]. CD8 T cell depletion studies using anti-CD8 antibodies [12–14] most likely reflect the loss of this innate immune response rather than a block in an adaptive immune response which should have eliminated the virus-infected cells. Enhancement of CNAR by co-administration of interleukin (IL)-2 or IL-15 [15,16] might increase the success of a vaccine.
The advantages of innate immunity for HIV infection are obvious:
it is a very rapid immune response to an incoming pathogen;
resistance to this type of response has not been described;
it is found at mucosal sites of HIV entry;
sequence diversity is not a problem as the response is pathogen-directed; and
this type of immunity, through cytokine production, signals a response of the adaptive immune system, that, as a concomitant partner, can play an important role in controlling HIV infection and disease progression.
Complete prevention of HIV infection via a vaccine will be extremely difficult to achieve . However, the initial infection could be controlled via vaccine strategies eliciting innate as well as adaptive immune responses that can reduce virus in blood and genital fluids and thus curtail HIV pathogenesis and transmission of the virus. Besides the potential beneficial role of γδ T cells induced by vaccines [6,7], encouraging results have been reported on antiviral responses and protection from infection using unmethylated oligonucleotide motifs (e.g., CpG) and heat-shock proteins (e.g., HSP 60) [3,6,18–20] with immunization. The approach with CpG most likely elicits a response by PDC.
Further studies directed at eliciting innate immunity, not generally considered in vaccine development, may be the novel approach that will determine the full effectiveness of an HIV vaccine. Importantly, this natural first line of defense once induced by a vaccine may make the difference between a rapidly spreading pathogenic course and one that moderates the infection and prevents transmission. The latter result is, after all, the major objective of a vaccine .
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