Current epidemiological data convincingly indicate that HIV infection is acquired predominantly by the mucosal route,
analogous with the majority of infectious diseases [1]. Mucosal surfaces of the genital and intestinal tracts are the major sites of
virus entry, yet major discoveries and advances in the technologies in the last decade alone have reinforced the importance of
examining mucosal immune responses. The earliest and most profound alterations of the immune system occur in mucosal
tissues of the intestinal tract, which constitute a crucial step in the pathogenesis of HIV [2, 3]. Furthermore, untreated HIV
patients are also usually infected by opportunistic mucosal pathogens of viral, bacterial, fungal and parasitic origin. The marked
quantitative and qualitative differences of the mucosal and systemic compartments of the immune system comprise the
dominant mucosal site of exposure to environmental antigens; phenotypically distinct cell populations including the antigenpresenting
dendritic cells, macrophages, epithelial cells, T and B lymphocytes, innate lymphoid cells, plasma cells; production
and selective transport of antibodies; and unique innate factors of immunity present in mucosal tissues and secretions. In
particular, HIV exploits the unique aspects of the mucosal immune system, especially its reservoir of activated CD4+ T target
cells, which support viral infection, amplification, mutation, and destruction of key immunoregulatory cells involved in
mucosal immunity. Loss of mucosal barrier integrity permits translocation of foreign antigens into the systemic circulation
resulting in further viral replication and continual seeding of viral reservoirs [3, 4]. Furthermore, the loss of immunoregulatory
T cells in mucosal tissues contributes to the lack of normal immune suppression, leading to increased levels of inflammation
supportive of continued HIV replication and persistence in tissues. Finally, mucosal tissues are increasingly recognized as the
major reservoir for viral persistence in patients on anti-retroviral therapy, especially in the Gut-Associated Lymphoid Tissues
(GALT) of the lower intestinal tract.
However, there are inherent difficulties in the collection and processing of mucosal specimens, including external secretions
with highly variable levels of humoral factors of immunity, or mucosal tissues with low yields of cells of interest. For these
reasons, current evaluations of immune responses to mucosal infections favor analyses of humoral factors and cells obtained
from peripheral blood, and only rarely consider mucosal sources. Further, differences in sample quality or timing may affect
results as mucosal tissues secrete a variety of proteases and nucleases, which can degrade their targets if not properly handled.
Nonetheless, in view of the demonstrable independence of the mucosal and systemic compartments of the immune system, the
scarcity of parallel evaluation of mucosal immune responses induced by infections or vaccination to date has provided only a
partial, and systemically biased glimpse of ensuing immune responses to vaccines or infections. This is certainly the case of
infection with HIV and SIV. The comparative studies of the mucosal and systemic immune compartments outlined in this
special issue provide a convincing picture of the uniqueness of the mucosal immune system with respect to humoral and
cellular responses and justify the regular inclusion of mucosal secretions and tissue as essential sources of information
especially for all HIV studies [3, 5, 6]. The marked immunological differences of the most frequent mucosal sites of virus entry,
the genital and intestinal tracts, with respect to the dominant Ig isotypes and their origin and the presence in the intestinal tract
of mucosal inductive sites must be considered in the development of effective HIV vaccines.
It is now clear that mucosal tissues play a major role in the pathogenesis of HIV infection. The profound depletion of
mucosal CD4+ T cells observed from the earliest stages of HIV/SIV infection irrespective of the route or transmission in both
the gastrointestinal and genital tracts has been related to the alteration of mucosal permeability and increased absorption of
mucosal antigens with continued stimulation of the immune system ultimately leading to its exhaustion. Although the early
events involved in transmission cannot be examined in humans, we know from nonhuman primate models that SIV and SHIV
selectively infect and selectively deplete activated CD4+CCR5+ and IL-17/IL-22-producing T cells (Th17/Th22) in the vaginal
mucosa. Th17 and Th22 cells are also rapidly depleted in the intestines of macaques, and since these subsets are believed to
play a major role in maintaining mucosal integrity, the loss of these key subsets may “set the stage” for the mucosal barrier
damage and subsequent systemic activation. This is accompanied by losses of T-regulatory cells, which are important for
moderating or suppressing immune responses [3, 6]. Finally, in organized gut- associated lymphoid tissues, T-follicular helper
cells (Tfh) are infected and dysregulated, which may result in problems with virus-specific antibody generation and maturation.
The CD4+ T-cell depletion is particularly interesting with respect to the T-cell-dependent differentiation of B cells into IgA- or
IgG-producing plasma cells. The HIV-infected individuals have increased total levels of plasma IgG and often IgA, but normal
levels of total Igs of all isotypes in external secretions; interestingly, HIV-specific IgA responses in these fluids are substantially diminished. Potential mechanisms involved in this puzzling observation have not been fully explained, but may be
linked to dysregulation of Tfh-cell and B-cell interactions in germinal centers of the GALT.
Taking into consideration the dominant mucosal sites of HIV entry, and profound immunological alterations of mucosal
tissues with distinct phenotypic heterogeneity of resident cells, the design and vaccination strategies should induce protective
responses at both genital and intestinal tracts as well as in the systemic compartment [5]. It is highly probable that a
combination of systemic and mucosal immunization routes will have to be implemented not only to induce desirable parallel
responses at all relevant sites but also to prevent the induction of mucosal tolerance defined as diminished or abolished
responsive T cells in the systemic compartment as a consequence of the initial exposure to antigens by a mucosal route.
Although mucosal immunization induces protective immune responses in all external sections due to the existence of the
common mucosal immune system, as well as in plasma, the impact on cell-mediated immunity, including cytotoxic T-cell
responses, has not been adequately explored. This may not be of importance for the majority of vaccines whose protective
effect is strictly antibody-mediated. However, in the case of HIV/SIV infection where T-cell immunity is also required, the
potential induction of mucosal tolerance must be considered.
We hope that this special thematic issue of the Current Immunology Reviews, with emphasis on the “Mucosal Immunology
of HIV/SIV”, will serve as a comprehensive source of essential information encompassing the majority of the key aspects
involved in the mucosal immunology of HIV/SIV infections. Rapidly emerging evidence indicates innate and possibly
noncanonical pathways of mucosal immunology may be critically involved in the prevention and control of HIV, and future
studies will lead to greater understandings of the cooperation of systemic and mucosal immune responses, establishment and
persistence of viral reservoirs, and provide new avenues for HIV prevention and cure research.
We thank and appreciate the contribution and patience of all authors, the editorial involvement of Ms. Patricia Grayson,
UAB, and the editorial staff of the publisher.
