Of molecules, macaques and global AIDS (2006)

HIV-1, which causes infection and disease exclusively in humans, is one of a growing number of viral pathogens where pathogenesis is being elucidated by quantification of viral nucleic acids, sequence analysis, and animal models with related and engineered, chimeric viruses. SIV is closely related to HIV-2 and provides a model primate retroviral infection with many parallels to that of HIV-1 in humans. Recent work with SIV is elucidating the course of early acute infection, including progression of genital track infection owing to local cytokine expression and cellular activation [1], tissue tropism [2], the early mucosal immune response [3], and the response to antiretroviral therapy [4]. By creating hybrids between HIV and SIV [5], the study presented by Centlivre et al. [6] has both elucidated pathogenic mechanisms in acute infection and provided a direct link between a regulatory gene in HIV-1 and the epidemiology of the global pandemic. Centlivre and colleagues have engineered a short piece of the HIV-1 promoter–enhancer from the HIV-1 3′ long terminal repeat into SIVmac239 to create SHIV chimerae [5]. Acute infection with short terminal repeat (STR) SHIV recapitulated the dynamics of acute HIV-1 infection, including acute viremia associated with a fall in circulating lymphocytes (as shown in Fig. 1b and 1a, respectively, of the report by Centlivre et al. [6]). Through serial measurements over the first weeks of infection and necropsy, they demonstrated early replication and amplification of SIV in gut-associated lymphoid tissue (GALT), including lamina propria lymphocytes, and in lymph nodes in the periphery and mesentery. This was associated with depletion of CD4+CCR5+ lymphocytes, predominantly memory T cells, as described for SIV infection in GALT [7]. Sequence and polymorphisms in the STR promoter/enhancer were conserved within subtypes and were distinct between HIV-1 subtypes B, C, and E. If macaques were infected simultaneously with the three chimeric viruses that were isogenic apart from the STR elements, distinct compartmental distribution, cellular distribution, and dynamics of provirus and viral RNA could be demonstrated among the competing subtype B, C, and E SHIV STR chimerae [5]. The three SHIV chimerae utilizing the STR from different HIV-1 subtypes showed distinct cellular and tissue distribution and kinetics of infection and viral replication. Peripheral blood sampled over the first weeks of infection had a predominance of subtype B STR virus as proviral DNA in mononuclear cells (PBMC), consistent with earlier findings in chronic infection, where subtype B STR predominated in PBMC, sera, and lymph nodes [5]. In contrast, early evidence of viremia included a transient burst of virus carrying subtype E STR, followed by the convincing predominance of subtype C virus, and little subtype B STR RNA over the first 2 weeks. This “disconnect” between the subtypes B, C, and E STR forms, the first as a provirus species, the latter two as actively replicating virus, suggests that subtype C STR and, to a lesser extent, subtype E STR contribute more efficiently to the earliest actively replicating virus. These findings are consistent with mucosal tissue cytokine expression and T cell activation as the drivers for SIV replication in GALT [1,2]. Plasma viral RNA in HIV-1 and SIV infection is thought to be the sum of virus replication in diverse lymphoid compartments that are largely separate from the circulating PBMC. In the study of Centlivre et al. [6], careful separation of specific gut lymphocytes, mesenteric and peripheral lymph nodes, and cells from lymphoid organs (see their Fig. 3) strongly suggests that the organized lymph nodes, peripherally as well as in the GALT, preferentially replicate subtype C STR virus, and this accounts for the predominance of STR C virus in plasma RNA during acute infection. The most prosaic (but perhaps important) result, the quantification of virus in the feces, clearly shows that subtype C virus is being expressed preferentially in the intestine, with abundant shedding into the lumen of the gut (see Fig. 4 of Centlivre et al. [6]). It is surprising that the inclusion of a relatively few bases from the STR of subtype C HIV-1 provides a dramatic competitive advantage for subtype C virus in plasma RNA during acute infection. In discussing a mechanism that might explain differences between clades in acute infection, Centlivre et al. [6] hypothesized that a non-cannonical activation protein (AP-1) binding site, identified in subtype C and E, could be responsible [5]. This is consistent with earlier in-vitro studies of the HIV-1 3′ long terminal repeat from different subtypes, which provided evidence for differences between subtypes B, C, and E virus by sequence and functional analysis of regulatory elements [8]. In cell culture and cell-free systems, multiple NF-κB-binding sites are more transcriptionally active in subtype C compared with subtype B and E virus [9]. The observation that subtype C and E viruses have a competitive advantage in acute infection is consistent with current thinking about the importance of recently infected individual to networks of sexual transmission, leading to differences in the incidence of HIV subtypes. Recently infected individuals, with high levels of viremia, genital shedding, and multiple concurrent partnerships, may contribute significantly to the sexual spread of HIV-1 in populations at risk [10,11]. Perhaps it is not coincidental that subtype C infection predominates in the most severely affected regions of the world [12]. The hypothesis that subtypes C may be more pathogenic and efficiently transmitted is based on the global distribution of subtypes and a few comparative studies of different subtypes in similar populations. However, the ascension and now dominance of subtype C HIV-1 infection in southern Africa, Ethiopia, and India is not well understood. Subtype C, and recombinants including elements of subtype C, are also making incursions in China, East Africa, and Brazil, where other subtypes have predominated. Centlivre et al. [6] have taken examination of the pathogenesis of acute infection and development of a SHIV model in macaques to a new level. Their careful experiment has identified the site(s) of virus infection and replication in GALT, the consequence of cytokine expression (particularly interleukin-7) on the relative fitness of three distinct, globally dominant subtypes, and, finally, they may have helped us to understand why the epidemic of certain HIV-1 subtypes seem to be getting rapidly ahead of prevention. They have successfully demonstrated the strength of the hypothesis that the STR elements provide an explanation for the relative fitness and replication of different subtypes in acute infection, providing insights into one of the puzzles of pathogenesis and the global epidemiology of HIV-1.