Abstract
With the advent of antiretroviral therapy that can control virus replication below the detection levels of conventional assays, a new clinical landscape of AIDS emerged, in which non-AIDS complications prevail over AIDS-defining conditions. These comorbidities are diverse and affect multiple organs, thus resulting in cardiovascular, kidney, neurocognitive and liver disease, osteopenia/osteoporosis, and cancers. A common feature of these conditions is that they are generally associated with accelerated aging. The mechanism behind these comorbidities is chronic excessive inflammation induced by HIV infection, which persists under antiretroviral therapy. Progressive simian immunodeficiency virus (SIV) infection of nonhuman primates (NHPs) closely reproduces these comorbidities and offers a simplified system in which most of the traditional human risk factors for comorbidities (i.e., smoking, hyperlipidemia) are absent. Additionally, experimental conditions can be properly controlled during a shorter course of disease for SIV infection. As such, NHPs can be employed to characterize new paradigms of AIDS pathogenesis and to test the efficacy of interventions aimed at alleviating non-AIDS-related comorbidities.
Highlights
With the advent of antiretroviral therapy that can control virus replication below the detection levels of conventional assays, a new clinical landscape of AIDS emerged, in which non-AIDS complications prevail over AIDS-defining conditions
In contrast to the natural hosts which do not present with CV lesions (Fig. 2a) the simian immunodeficiency virus (SIV)/pigtailed macaques (PTMs) model closely reproduces the spectrum of CVabnormalities reported in HIVinfected patients, i.e., thrombotic microangiopathy (TMA), arteriopathy, myocardial hypertrophy and fibrosis, atherosclerosis (ATS), infarction, and myocarditis [77,78,79,80]
We have recently confirmed similar features in SIVsab-infected PTM, our model of pathogenic SIV infection, in which we identified histological lesions similar to HIV-associated nephropathy (HIVAN), i.e., the hyperplasia of the epithelial lining of the Bowman capsule (Fig. 1e) associated with collapsing/ glomerulosclerosis glomerulopathy (Fig. 1e), diffuse (Fig. 1f) or pseudogranulomatous (Fig. 1g) interstitial nephritis associated with dilated microtubules containing either hyaline (Fig. 1h) or cellular casts (Fig. 1i)
Summary
The advent of antiretroviral therapies (ART) is one of the most prominent accomplishments of modern medicine, which dramatically changed the clinical landscape of human immunodeficiency virus (HIV) infection. Comparative studies between pathogenic SIV infections in macaques and nonpathogenic SIV infections in their natural hosts (i.e., sooty mangabeys and AGMs) decisively contributed to the new paradigms of HIV pathogenesis in which chronic immune activation, dysfunction of the lymphoid tissues, and preferential depletion/preservation of different CD4+ T cell subsets are key contributors to AIDS progression [18, 9] In this context, one of the key questions in the field is whether or not NHP models will be useful to study the HIV comorbidities that form the current clinical landscape of AIDS. In HIV-infected patients, microbial translocation has characteristic features: generalized immune activation is associated with preferential loss of cell subsets involved in maintaining epithelial integrity at mucosal surfaces and antimicrobial immunity, such as the CD4+ T cells secreting IL-17 and IL-22 [53, 54] These features were established by comparative studies of the pathogenesis of SIV infection in progressive and nonprogressive animal models. None of these studies provided a clear clinical improvement, but they collectively provided strong support for pursuing interventions aimed at alleviating the GI alterations in order to improve the clinical outcome of HIV infection
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