HIV-2 infection is highly prevalent in West Africa and has been increasingly observed in non-African countries, mostly associated with migratory populations . It has a much more benign course and lower viremia than HIV-1 , though with similar clinical spectra. Half of the HIV-2 infected patients with less than 200 CD4+ T-cells/μl exhibit undetectable viremia, despite harbouring numbers of infected cells comparable to their HIV-1 counterparts . Moreover, CD4+ T-cell loss occurs in direct association with progressive immune activation in both infections, though the depletion rate is much slower in HIV-2 [2,4]. HIV-1 disease progression has been linked to disruption of gut-associated lymphoid tissue (GALT) and increased levels of microbial translocation, leading to systemic immune activation. There are currently no data on the impact of HIV-2 on GALT. Here, we provide evidence of HIV-2 replication in the gut despite the low viremia, which was associated with major mucosal disruption and CD4+ T-cell depletion that recovered upon antiretroviral treatment (ART).
An 18-year-old man, from Guinea-Bissau, with HIV-2 infection possibly acquired by vertical transmission, presented with mild diarrhoea since the first year of life. Colonoscopy showed loss of haustra and rectal ulcers, with moderate lymphoplasmocytic and neutrophilic infiltrates in rectal biopsies (Fig. 1a,b). Circulating CD4+ T-cells were low (19%, 103 cells/μl), in association with hyperimmune activation (Fig. 1c) and detectable viremia (4575 RNAcopies/ml), albeit at levels much lower than those found in HIV-1 infection. There was a significant depletion of CD4+ T-cells and an increase in CD8 T-cells in sigmoid lamina propria (Fig. 1a). This ratio inversion was associated with increased regulatory T-cells (Treg, FOXP3+) and decreased interleukin (IL)-17 producing cells (Fig. 1a), an immunological profile strikingly similar to that described for HIV-1 infected individuals.
These gut disturbances were accompanied by an increase in serum markers usually linked with high levels of microbial translocation, assessed as previously described : plasma lipopolysaccharide (136 pg/ml), serum lipopolysaccharide binding protein (1.2 μg/ml) and soluble-CD14 (3.2 μg/ml), as well as systemic immune activation (Fig. 1c). Thus, our findings support a contribution of microbial translocation to HIV-2 pathogenesis, adding to this ongoing debate [5,6].
Local viral replication is considered a main determinant of HIV-1 associated mucosal disturbances. We found expression of HIV-2 Gag protein in different colon segments (Fig. 1d), which supports a significant degree of mucosal HIV-2 replication, despite the low viremia. This is in line with our previous findings of ongoing viral replication in HIV-2 patients with undetectable circulating virus, and similar levels of cell-associated viral burden in the two infections .
ART (emtricitabine/tenofovir/saquinavir/ritonavir) was initiated with clear virological (undetectable viremia) and immunological responses (845 CD4+ T-cells/μl, 25.5%; 1-year post-ART), accompanied by a progressive decline in systemic activation markers (Fig. 1c). Notably, our patient presented a marked delay of puberty (bone age of 12.5 years), and, similar to HIV-1 infected children, an interstitial lymphoid pneumonia that fully resolved with therapy.
Conversely, diarrhoea persisted with exacerbation of inflammatory histologic findings (transmural chronic inflammatory infiltrate with lymphoid aggregates, sparse noncaseating granulomas and mucosal architectural distortion), mimicking Crohn's disease, leading to the development of rectal stenosis that required endoscopic dilatations and segmental resection (Fig. 1a,b). In spite of these disturbances, there was a recovery of lamina propria lymphocyte imbalances (Fig. 1a), as well as lack of evidence of HIV-2 replication (Gag expression, data not shown). It is plausible that this paradoxical evolution represents a form of late immunological reconstitution disease because, at that time, there was already a recovery of mucosal CD4+ T-cells and IL-17 production (Fig. 1a). Gut manifestations disappeared after prolonged ART, with sustained immunological response, both in gut mucosa (Fig. 1a) and peripheral blood (716 CD4+ T-cells/μl, 48.1%; 5 years post-ART).
Thus, our results represent a rational basis for starting ART in HIV-2 infection irrespectively of viremia. There are currently no randomized trials addressing ART in HIV-2 infected individuals . Longitudinal studies suggest that HIV-2 infected patients have a limited response to ART, specifically a reduced CD4+ T-cell recovery as compared with HIV-1 [2,3]. This might be related to virologic inefficacy, as antiretroviral drugs have not been specifically designed for HIV-2, and genotypic and phenotypic resistance studies are limited precluding an adequate choice of the best regimens . Alternatively, the prolonged course of HIV-2 disease might lead to irreversible damage of secondary lymphoid organs, thereby preventing complete immunological recovery.
In conclusion, this is the first study of mucosal CD4+ T-cell depletion with loss of IL-17 producing cells in HIV-2 infection, which was shown to recover upon suppression of ongoing low-level viral replication with ART. Our results represent an argument in favour of treating HIV infection in the context of reduced viremia.
S.M.F., A.R.P., C.F. and RT performed research; S.M.F., L.C. and S.E.P. did the collection of clinical data; S.M.F., R.M.M.V. and A.E.S designed the study, analysed data and wrote the article.
This work was supported by the Fundação para a Ciência e Tecnologia (FCT), and the Programa Operacional Ciência e Inovação 2010 (PIC/IC/82712/2007 to A.E.S.). S.M.F., A.R.P. and R.T. received FCT scholarships.
Conflicts of interest
There are no conflicts of interest.
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