T cell activation levels, viral load and CD4+ T cell counts at early stages of HIV-1 infection are predictive of the rate of progression towards AIDS. We evaluated whether the inflammatory profile during primary HIV-1 infection is predictive of the virological and immunological set-points and of disease progression. We quantified 28 plasma proteins during acute and post-acute HIV-1 infection in individuals with known disease progression profiles. Forty-six untreated patients, enrolled during primary HIV-1 infection, were categorized into rapid progressors, progressors and slow progressors according to their spontaneous progression profile over 42 months of follow-up. Already during primary infection, rapid progressors showed a higher number of increased plasma proteins than progressors or slow progressors. The plasma levels of TGF-β1 and IL-18 in primary HIV-1 infection were both positively associated with T cell activation level at set-point (6 months after acute infection) and together able to predict 74% of the T cell activation variation at set-point. Plasma IP-10 was positively and negatively associated with, respectively, T cell activation and CD4+ T cell counts at set-point and capable to predict 30% of the CD4+ T cell count variation at set-point. Moreover, plasma IP-10 levels during primary infection were predictive of rapid progression. In primary infection, IP-10 was an even better predictor of rapid disease progression than viremia or CD4+ T cell levels at this time point. The superior predictive capacity of IP-10 was confirmed in an independent group of 88 HIV-1 infected individuals. Altogether, this study shows that the inflammatory profile in primary HIV-1 infection is associated with T cell activation levels and CD4+ T cell counts at set-point. Plasma IP-10 levels were of strong predictive value for rapid disease progression. The data suggest IP-10 being an earlier marker of disease progression than CD4+ T cell counts or viremia levels.

Chronic immune activation (IA) is considered as the driving force of CD4+ T cell depletion and AIDS. Fundamental clues in the mechanisms that regulate IA could lie in natural hosts of SIV, such as African green monkeys (AGMs). Here we investigated the role of innate immune cells and IFN-α in the control of IA in AGMs. AGMs displayed significant NK cell activation upon SIVagm infection, which was correlated with the levels of IFN-α. Moreover, we detected cytotoxic NK cells in lymph nodes during the early acute phase of SIVagm infection. Both plasmacytoid and myeloid dendritic cell (pDC and mDC) homing receptors were increased, but the maturation of mDCs, in particular of CD16+ mDCs, was more important than that of pDCs. Monitoring of 15 cytokines showed that those, which are known to be increased early in HIV-1/SIVmac pathogenic infections, such as IL-15, IFN-α, MCP-1 and CXCL10/IP-10, were significantly increased in AGMs as well. In contrast, cytokines generally induced in the later stage of acute pathogenic infection, such as IL-6, IL-18 and TNF-α, were less or not increased, suggesting an early control of IA. We then treated AGMs daily with high doses of IFN-α from day 9 to 24 post-infection. No impact was observed on the activation or maturation profiles of mDCs, pDCs and NK cells. There was also no major difference in T cell activation or interferon-stimulated gene (ISG) expression profiles and no sign of disease progression. Thus, even after administration of high levels of IFN-α during acute infection, AGMs were still able to control IA, showing that IA control is independent of IFN-α levels. This suggests that the sustained ISG expression and IA in HIV/SIVmac infections involves non-IFN-α products.

HIV infects activated CD4 ؉ T cells and induces their depletion. Progressive HIV infection leading to AIDS is fueled by chronic immune hyperactivation, mediated by inflammatory cytokines like TNF␣. This has been related to intestinal epithelial damage and microbial LPS translocation into the circulation. Using 11-color flow cytometry, cell sorting, and cell culture, we investigated the numbers and TNF␣ production of fully defined circulating dendritic cell and monocyte populations during HIV-1 infection. In 15 viremic, untreated patients, compared with 8 treated, virologically suppressed patients or to 13 healthy blood donors, circulating CD141 (BDCA-3) ؉ and CD1c (BDCA-1) ؉ dendritic cell counts were reduced. Conversely, CD14 ؉ CD16 ؉؉ monocyte counts were increased, particularly those expressing M-DC8, while classical CD14 ؉؉ CD16 ؊ M-DC8 ؊ monocyte numbers were unchanged. Blood mononuclear cells from viremic patients produced more TNF␣ in response to LPS than those from virologically suppressed patients. M-DC8 ؉ monocytes were mostly responsible for this overproduction. Moreover, M-DC8 ؉ monocytes differentiated in vitro from classical monocytes using M-CSF and GM-CSF, which is increased in viremic patient's plasma. This M-DC8 ؉ monocyte population, which is involved in the pathogenesis of chronic inflammatory diseases like Crohn disease, might thus be considered as a major actor in the immune hyperactivation fueling HIV infection progression. (Blood. 2012;120(11): 2259-2268) IntroductionHIV-1 infection induces the depletion of CD4 ϩ T lymphocytes in blood and lymphoid organs, particularly in the gut-associated lymphoid tissue. [1][2][3] The absence of immune activation during the chronic phase of the infection distinguishes nonprogressive from progressive infections in patients as well as in nonhuman primate models of HIV infection. [4][5][6] Systemic immune activation is correlated to the increased translocation of gut luminal microbial products such as the Gram-negative bacterial lipopolysaccharide (LPS). 7 LPS stimulates the production of proinflammatory cytokines, particularly TNF␣. In HIV-1-infected patients, TNF␣ serum levels increase in correlation with disease progression and drop to normal levels after treatment only in patients with good virologic and immunologic responses. 3,8 By activating the NF-B pathway, TNF␣ induces viral replication in HIV-infected CD4 ϩ T lymphocytes. 3,9 In chronic inflammatory bowel diseases, TNF␣ affects mucosal integrity, leading to microbial product systemic translocation. 10 Granulocyte/macrophage colony-stimulating factor (GM-CSF) and LPS also induce HIV replication in infected myeloid cells. 11,12 GM-CSF and TNF␣ are produced by monocytes and dendritic cells (DCs) after LPS stimulation.During chronic HIV infection, circulating plasmacytoid and myeloid DC (pDC and mDC) numbers are reduced. [13][14][15] Myeloid DCs were mostly studied in HIV-infected patients using CD11c as a marker. Now, they are further subdivided into BDCA-1 ϩ and BDCA-3 ϩ mDC subsets, the latter r...