Current HIV Research - Volume 7, Issue 1, 2009

The etiologic agent that causes human AIDS was identified in 1981. Only a few years later Rhesus macaques at the New England Primate Center were observed exhibiting clinical signs representative of AIDS, leading to the isolation and identification of the simian immunodeficiency virus (SIV). Since that time, numerous studies have been undertaken utilizing the SIV/monkey model and a range of pathogenic outcomes identified due to genetic, virologic and immunologic differences. The distinct disease outcomes are quite evident when assessing the SIV infection in different monkey species. The majority of monkey species in Africa harbor SIV infections in the wild, and have been termed SIV natural host species. Sooty mangabeys (West Africa) and African green monkeys (found throughout Africa) are two of the more commonly studied SIV natural hosts. SIV is able to replicate to high levels in the natural host species yet the virus and host generally coexist, without exhibiting any clinical signs of simian AIDS. In contrast, macaques are from Asia and are not naturally infected with SIV in the wild. Therefore, SIV infection of macaques represent a cross-species transmission of the virus and in this regard is similar to HIV in humans. The SIV infection of macaques is similar to infectio of natural hosts as it also results in high levels of viral replication, however there are also clear indications of immune dysfunction commonly seen in AIDS patients (CD4 T cell decline, wasting, opportunistic infections). Although a small number of macaques are able to resist progression to AIDS, the vast majority of SIV infected macaques develop AIDS clinical signs and die by 6 months to 2 years post-infection. In this issue of Current HIV Research, three reviews assess various aspects of the infection of natural host species. Liovat et al. provide a clear assessment of the similarities and differences between the SIV infection in pathogenic and nonpathogenic primate hosts. One of the key findings is that during the earliest times post-infection SIV infections are similar in all species, however nonpathogenic infections distinguish themselves during the chronic phase of the infection when elements of immune activation and subsequent immune dysfunction are suppressed. Pereira and Ansari expanded upon the natural host analysis by assessing the role of innate cell subsets, NK cells and DCs, in keeping natural host species from progressing to AIDS. Pandrea et al. provide a more complete understanding of the nonpathogenic infection models by providing evidence that these host species can, under some circumstances develop clinical signs of simian AIDS. Based on these rare cases in more aged nonpathogenic species the authors of this review suggest that we should more accurately refer to natural hosts of SIV as being ‘persistently nonprogressive’. Six of the reviews assess and provide key insights into the pathogenic SIV infection of macaques. While the reviews have an overall focus that is immunologic in nature, they also provide information with regard to how the SIV infection itself is the trigger and underlying force that propels SIV-positive macaques toward simian AIDS. Cheng-Mayer et al. describe how coreceptor utilization impacts disease progression in the SIV/SHIV model, with a focus on the impact of coreceptor switching. Abel assesses the SIV macaque model for its use for studying pediatric SIV infections addressing aspects of transmission and immunologic implications of SIV/HIV infection of newborns. The ability of SIV/HIV infections to impact the functionality of plasmacytoid DCs is investigated by Wijewardana et al. Whereas Reinhart et al. focus on how dysregulation of chemokines impacts disease progression in SIV infected macaques. Burwitz et al. describe how studying Mauritian Cynomolgus macques, which have simple MHC genetics, might provide a model for utilizing lymphocyte adoptive transfer studies to better understand how to improve vaccine design. And finally, Leone et al. describes how cytokines that can impact T cell homeostasis are being utilized as both immune therapeutics and vaccine immune modulators in the SIV macaque model.

Worldwide, the AIDS pandemic continues almost relentlessly. Women are now representing the fastest growing group of newly infected HIV-1 infected patients. The risk of mother-to-child-transmission (MTCT) of HIV-1 increases proportionally as many of these women are of childbearing age. The screening of pregnant women, the early diagnosis of HIV-1 infection, and the administration of antiretroviral therapy (ART) have helped to reduce MTCT significantly. However, this holds true only for developed countries. In many resource-poor countries, access to ART is limited, and breastfeeding, a major route of HIV-1 transmission, is essential to protect the infant from other infectious diseases preponderant in those geographic regions. HIV-1 infected children, in contrast to adult patients, have higher levels of virus replication that decline only slowly, and a subset progresses to AIDS within the first two years. Thus, it is imperative to understand pediatric HIV-1 pathogenesis to design effective prevention strategies and/or a successful pediatric HIV-1 vaccine. The review summarizes how MTCT of HIV-1 in humans can be modeled in the infant macaque model of SIV infection. Importantly, the infant macaque model of SIV infection provides the opportunity to study early virus-host interactions in multiple anatomic compartments. Furthermore, the review underlines the importance of evaluating SIV/HIV immune responses in the context of the normal developmental changes the immune system undergoes in the newborn. Thus, the pediatric SIV infection model provides a unique resource for preclinical studies of novel intervention therapies and vaccine strategies to stop MTCT of HIV-1.

Natural or experimental infection of the African sooty mangabey (SM) with the simian immunodeficiency virus (SIV) results in chronic high levels of virus replication but is associated with none of the debilitating immunopathology, including the marked CD4 T-cell depletion, persistent cell activation and acquired immunodeficiency, that afflicts nonnatural hosts such as SIV-infected Asian rhesus macaques (RM) and HIV-infected humans. Although SIV-infected RM have served as important models of AIDS given their remarkably similar course of disease to HIV-infected humans, deciphering the immune mechanisms that enable SIV-infected SM to resist disease development despite high viremia has yet to be defined. Intense studies for the past two decades using these nonhuman primate models have been conducted with the hope that this will yield better insight into the pathogenesis of AIDS, translating into the development of therapeutic strategies for HIV-infected individuals such as but not limited to identifying correlates of protective immunity that can be harnessed for the preparation of effective vaccines. Although much has been reported about SIV-specific adaptive immune responses in both the natural and unnatural hosts of SIV, we submit that innate immunity may play a larger than previously appreciated role in SIV pathogenesis, in particular during the period of acute infection. The purpose of this review is to therefore highlight the recent advances that have been made in understanding innate immune responses in SIVinfected SM and to discuss the role(s) of the major innate immune cell lineages that potentially contribute to disease resistance in this non-human primate species.

Plasmacytoid dendritic cells (pDC) play a key role in antiviral immunity through their immense capacity to produce type I interferons (IFN) and other cytokines and through induction of antigen-specific T cell responses. Several reports have documented decreased numbers and reduced function of pDC in the circulation of HIV patients associated with progression to disease, indicating that pDC are likely to be important in control of HIV infection. The mechanism of pDC loss has not been determined and is difficult to address in natural infection of humans. As highlighted in this brief review, the study of pDC dynamics in simian immunodeficiency virus (SIV) infection of nonhuman primates paves the way to understanding the complex biology of this important innate system cell in HIV and other viral infections.

The human immunodeficiency virus (HIV) enters target cells via interaction of the viral glycoprotein with the cellular receptor CD4 and two principal coreceptors, CCR5 (R5 viruses) and CXCR4 (X4 viruses). Most HIV-1 transmissions result in a predominantly R5 virus infection. With time, X4 variants arise and coexist with R5 virus variants in ∼50% of subtype B infected individuals. The underlying basis for virus coreceptor switch late in infection remains an enigma, but will be important to understand given that the appearance of X4 virus in HIV-1 infected patients inevitably heralds an unfavorable clinical outcome. Recently, emergence of X4 viruses was observed in rhesus macaques experimentally infected with a CCR5-tropic simian-human immunodeficiency virus (SHIV) with progression to disease, providing some insights into the process of coreceptor switching in vivo. Further studies in this animal model should enhance our understanding of the mechanistic basis for, and obstacles to, coreceptor switch.

African non human primates are natural hosts of SIV. The infection is generally non-pathogenic despite high steady-state levels of plasma viral RNA that in HIV-1 and SIVmac infections are associated with progression towards AIDS. The viral loads in the gut also are as high as in pathogenic HIV-1/SIVmac infections; but replication levels are lower in peripheral lymph nodes of chronically infected African green monkeys. There is a transient loss of CD4+ T cells in the blood in SIVagm and SIVsm infections and an early dramatic and more persistent decrease in the gut. Although SIV in natural hosts is thus cytopathic, the continuous viral replication is not associated with immunopathology. T CD4+ cells in blood, lymph nodes and gut manifest no or little increase of cell-death by apoptosis. The lymph node and gut architecture is not disrupted. The most striking difference between non-pathogenic SIV and pathogenic HIV-1/SIVmac infections is the lack of chronic T cell activation. Several studies are currently in progress to determine which factors are involved in the maintenance of the low activation level in the non-pathogenic SIV infections. There are two ways in which this could be achieved: (i) a lack of immune activation induction or (ii) an active downregulation of the immune activation. The arguments in favor of each of these two possible ways of immune activation control will be discussed in view of the most recent data in the literature. A particular focus is put on data on the innate immune system and the timing of induction of immunosuppressive mediators during the early phase of SIV infection.

An HIV vaccine remains elusive despite the concerted efforts of investigators and clinicians over the past two decades. Animal models are regularly used to obtain new insights on disease pathogenesis and have become invaluable tools in the translation of treatments from basic research laboratories to the clinic. Vaccination of macaques with live, attenuated simian immunodeficiency virus is currently the most effective method of garnering protection against subsequent pathogenic SIV challenge. However, immunization of humans with live, attenuated HIV is not feasible due to safety concerns. Therefore, clues to an effective and safe vaccine against HIV may be found by studying immune correlates of protection in the live, attenuated, vaccinated macaque model. Previous studies have identified the immune correlates of protection against Friend retrovirus in live, attenuated vaccinated mice using allogeneic adoptive transfers. Similar experiments in macaques have thus far been hindered due to the vast genetic diversity found within outbred populations. Here we review the current state of SIV adoptive transfer research and present a novel macaque model that allows for allogeneic adoptive transfers.

It is generally considered that African nonhuman primates (NHPs) do not progress to AIDS. In the wild, due to either a shorter life span or an insufficient follow-up of the animals, no AIDS cases were described to date. However, in captivity, at least one case of immunodeficiency was reported for each of the currently available models of natural infection (African green monkey, sooty mangabey and mandrill). Furthermore, experimental infection of three other African NHP species, the black mangabey (BkM), the chimpanzee and the baboon with heterologous viruses, such as SIVsmm, HIV-1 and HIV-2, respectively also resulted in progression to AIDS. Here, we present the clinical, pathologic and virologic findings of these cases of progressive disease in African NHP hosts. Similar to pathogenic infections of humans and rhesus macaques, progression to AIDS in natural hosts is characterized by: CD4+ T cell depletion in peripheral blood and intestine, opportunistic infections and neoplasia, severe weight loss, lymphocytic interstitial pneumonia, lymphoid tissue hypoplasia, and giant cell disease. Importantly, in these animals the set point levels of viral loads (VLs) were higher than in the majority of naturally-infected African NHPs, with significant increases of VLs occurring in association with disease progression. Finally, African NHP progressors showed increased levels of immune activation and cell proliferation, which differentiate them from the vast majority of African NHPs in which immune activation is not significantly increased during the chronic SIV infection compared to their SIV uninfected counterparts. Despite the rarity of AIDS cases in African NHPs, the spectrum and morphology of the observed lesions are very similar to those encountered in humans or macaques with AIDS. Therefore, we suggest that the “nonpathogenic” models of SIV infection should be reconsidered as “persistently nonprogressive” SIV infections. The fact that SIV-infected African NHPs may, in fact, occasionally progress to AIDS emphasizes the importance of studying these models to better understand AIDS pathogenesis and design new therapeutic and preventative interventions for HIV infection.

Chemokines are small chemoattractant cytokines involved in homeostatic and inflammatory immune cell migration. These small proteins have multiple functional properties that extend beyond their most recognized role in controlling cellular migration. The complex immunobiology of chemokines, coupled with the use of subsets of chemokine receptors as HIV-1 and SIV entry co-receptors, suggests that these immunomodulators could play important roles in the pathogenesis associated with infection by HIV-1 or SIV. This review provides an overview of the effects of pathogenic infection on chemokine expression in the SIV/macaque model system, and outlines potential mechanisms by which changes in these expression profiles could contribute to development of disease. Key challenges faced in studying chemokine function in vivo and new opportunities for further study and development of therapeutic interventions are discussed. Continued growth in our understanding of the effects of pathogenic SIV infection on chemokine expression and function and the continuing development of chemokine receptor targeted therapeutics will provide the tools and the systems necessary for future studies of the roles of chemokines in HIV-1 pathogenesis.

While highly active antiretroviral therapy (HAART) regimens have proven to be effective in controlling active HIV replication, complete recovery of CD4+ T cells does not always occur, even among patients with high level virologic control. Recent advances in understanding the biology of T cell production and homeostasis have created the potential to augment anti-viral therapies with immunotherapies designed to facilitate recovery of the HIV-damaged immune system, in particular, the recovery of CD4+ T cell populations. The common gamma-chain cytokines IL-2, IL-7 and IL-15 are primary regulators of T cell homeostasis and thus have been considered prime candidate immunotherapeutics, both for increasing T cell levels/function and for augmenting vaccine-elicited viral-specific T cell responses. Recent studies have established that these cytokines have distinct functional roles in immune homeostasis, which focus on specific T cell populations. The ability of these cytokines to provide immunotherapeutic benefit to HIV+ patients will depend on their ability to stably increase or functionally enhance the desired T cell target population without adverse virologic or clinical consequences.

The human immunodeficiency virus (HIV-1) differentially controls viral protein expression at the level of splicing as well as nuclear export of incompletely spliced viral RNA. This process, mediated by the Rev protein, interfaces with cellular components involved in post-transcriptional gene regulation. While a number of reviews have focused on the host proteins (i.e., Crm1, importin-β and nucleoporins) that specifically regulate shuttling of Rev between the nucleus and cytoplasm, we could find no systematic review of other cellular proteins implicated in Rev function. Therefore, we will here focus on other Rev cofactors (eIF5a, hRIP, Sam68, RNA helicases, etc) and the role they play in Rev/RRE function and HIV-1 replication.

The HIV-1 Rev protein, which traffics through nucleolus and shuttles between nucleus and cytoplasm, facilitates export of unspliced and singly spliced viral transcripts containing RRE RNA by the CRM1 export pathway. Inhibitions of the various stages of Rev-mediated RNA transport can arrest HIV-1 transcriptional process. The current understanding to the mechanism of Rev function, Rev-RRE interaction, as well as inhibitors hereof is reviewed.