Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 63
Filter
1.
Cell Rep ; 32(12): 108174, 2020 09 22.
Article in English | MEDLINE | ID: mdl-32966788

ABSTRACT

Highly efficient CD8+ T cells are associated with natural HIV control, but it has remained unclear how these cells are generated and maintained. We have used a macaque model of spontaneous SIVmac251 control to monitor the development of efficient CD8+ T cell responses. Our results show that SIV-specific CD8+ T cells emerge during primary infection in all animals. The ability of CD8+ T cells to suppress SIV is suboptimal in the acute phase but increases progressively in controller macaques before the establishment of sustained low-level viremia. Controller macaques develop optimal memory-like SIV-specific CD8+ T cells early after infection. In contrast, a persistently skewed differentiation phenotype characterizes memory SIV-specific CD8+ T cells in non-controller macaques. Accordingly, the phenotype of SIV-specific CD8+ T cells defined early after infection appears to favor the development of protective immunity in controllers, whereas SIV-specific CD8+ T cells in non-controllers fail to gain antiviral potency, feasibly as a consequence of early defects imprinted in the memory pool.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , Cell Proliferation , Chronic Disease , Haplotypes/genetics , Immunologic Memory , Lymph Nodes/pathology , Lymphocyte Count , Macaca fascicularis , Major Histocompatibility Complex , Simian Acquired Immunodeficiency Syndrome/blood , Viremia
2.
Cell Death Differ ; 27(12): 3243-3257, 2020 12.
Article in English | MEDLINE | ID: mdl-32514048

ABSTRACT

Understanding the viral-host cell interface during HIV-1 infection is a prerequisite for the development of innovative antiviral therapies. Here we show that the suppressor of G2 allele of skp1 (SUGT1) is a permissive factor for human immunodeficiency virus (HIV)-1 infection. Expression of SUGT1 increases in infected cells on human brain sections and in permissive host cells. We found that SUGT1 determines the permissiveness to infection of lymphocytes and macrophages by modulating the nuclear import of the viral genome. More importantly, SUGT1 stabilizes the microtubule plus-ends (+MTs) of host cells (through the modulation of microtubule acetylation and the formation of end-binding protein 1 (EB1) comets). This effect on microtubules favors HIV-1 retrograde trafficking and replication. SUGT1 depletion impairs the replication of HIV-1 patient primary isolates and mutant virus that is resistant to raltegravir antiretroviral agent. Altogether our results identify SUGT1 as a cellular factor involved in the post-entry steps of HIV-1 infection that may be targeted for new therapeutic approaches.


Subject(s)
Cell Cycle Proteins/metabolism , HIV-1/metabolism , Microtubule-Associated Proteins/metabolism , Microtubules/metabolism , Acetylation , Active Transport, Cell Nucleus/genetics , Anti-HIV Agents/therapeutic use , Cell Cycle Proteins/genetics , Drug Resistance, Viral/genetics , HIV Infections/drug therapy , HIV-1/genetics , Humans , Microtubule-Associated Proteins/genetics , Microtubules/genetics , Microtubules/pathology , Raltegravir Potassium/therapeutic use , Virus Replication
3.
Cell Rep ; 28(13): 3381-3394.e7, 2019 09 24.
Article in English | MEDLINE | ID: mdl-31553908

ABSTRACT

Purinergic receptors and nucleotide-binding domain leucine-rich repeat containing (NLR) proteins have been shown to control viral infection. Here, we show that the NLR family member NLRP3 and the purinergic receptor P2Y2 constitutively interact and regulate susceptibility to HIV-1 infection. We found that NLRP3 acts as an inhibitory factor of viral entry that represses F-actin remodeling. The binding of the HIV-1 envelope to its host cell receptors (CD4, CXCR4, and/or CCR5) overcomes this restriction by stimulating P2Y2. Once activated, P2Y2 enhances its interaction with NLRP3 and stimulates the recruitment of the E3 ubiquitin ligase CBL to NLRP3, ultimately leading to NLRP3 degradation. NLRP3 degradation is permissive for PYK2 phosphorylation (PYK2Y402∗) and subsequent F-actin polymerization, which is required for the entry of HIV-1 into host cells. Taken together, our results uncover a mechanism by which HIV-1 overcomes NLRP3 restriction that appears essential for the accomplishment of the early steps of HIV-1 entry.


Subject(s)
Actins/metabolism , HIV-1/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Humans , Polymerization , Signal Transduction , Virus Internalization
4.
Nat Metab ; 1(7): 704-716, 2019 07.
Article in English | MEDLINE | ID: mdl-32694646

ABSTRACT

Spontaneous control of human immunodeficiency virus (HIV) is generally associated with an enhanced capacity of CD8+ T cells to eliminate infected CD4+ T cells, but the molecular characteristics of these highly functional CD8+ T cells are largely unknown. In the present study, using single-cell analysis, it was shown that HIV-specific, central memory CD8+ T cells from spontaneous HIV controllers (HICs) and antiretrovirally treated non-controllers have opposing transcriptomic profiles. Genes linked to effector functions and survival are upregulated in cells from HICs. In contrast, genes associated with activation, exhaustion and glycolysis are upregulated in cells from non-controllers. It was shown that HIV-specific CD8+ T cells from non-controllers are largely glucose dependent, whereas those from HICs have more diverse metabolic resources that enhance both their survival potential and their capacity to develop anti-HIV effector functions. The functional efficiency of the HIV-specific CD8+ T cell response in HICs is thus engraved in their memory population and related to their metabolic programme. Metabolic reprogramming in vitro through interleukin-15 treatment abrogated the glucose dependency and enhanced the antiviral potency of HIV-specific CD8+ T cells from non-controllers.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV Infections/prevention & control , HIV-1/immunology , Humans
5.
J Virol ; 91(23)2017 12 01.
Article in English | MEDLINE | ID: mdl-28931685

ABSTRACT

HIV-1 infection of noncycling cells, such as dendritic cells (DCs), is impaired due to limited availability of deoxynucleoside triphosphates (dNTPs), which are needed for HIV-1 reverse transcription. The levels of dNTPs are tightly regulated during the cell cycle and depend on the balance between dNTP biosynthesis and degradation. SAMHD1 potently blocks HIV-1 replication in DCs, although the underlying mechanism is still unclear. SAMHD1 has been reported to be able to degrade dNTPs and viral nucleic acids, which may both hamper HIV-1 reverse transcription. The relative contribution of these activities may differ in cycling and noncycling cells. Here, we show that inhibition of HIV-1 replication in monocyte-derived DCs (MDDCs) is associated with an increased expression of p21cip1/waf, a cell cycle regulator that is involved in the differentiation and maturation of DCs. Induction of p21 in MDDCs decreases the pool of dNTPs and increases the antiviral active isoform of SAMHD1. Although both processes are complementary in inhibiting HIV-1 replication, the antiviral activity of SAMHD1 in our primary cell model appears to be, at least partially, independent of its dNTPase activity. The reduction in the pool of dNTPs in MDDCs appears rather mostly due to a p21-mediated suppression of several enzymes involved in dNTP synthesis (i.e., RNR2, TYMS, and TK-1). These results are important to better understand the interplay between HIV-1 and DCs and may inform the design of new therapeutic approaches to decrease viral dissemination and improve immune responses against HIV-1.IMPORTANCE DCs play a key role in the induction of immune responses against HIV. However, HIV has evolved ways to exploit these cells, facilitating immune evasion and virus dissemination. We have found that the expression of p21, a cyclin-dependent kinase inhibitor involved in cell cycle regulation and monocyte differentiation and maturation, potentially can contribute to the inhibition of HIV-1 replication in monocyte-derived DCs through multiple mechanisms. p21 decreased the size of the intracellular dNTP pool. In parallel, p21 prevented SAMHD1 phosphorylation and promoted SAMHD1 dNTPase-independent antiviral activity. Thus, induction of p21 resulted in conditions that allowed the effective inhibition of HIV-1 replication through complementary mechanisms. Overall, p21 appears to be a key regulator of HIV infection in myeloid cells.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/metabolism , Dendritic Cells/virology , Deoxyribonucleotides/biosynthesis , HIV-1/physiology , Monocytes/virology , SAM Domain and HD Domain-Containing Protein 1/metabolism , Antiviral Agents/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , DNA Replication , Dendritic Cells/physiology , Deoxyribonucleotides/chemistry , HIV-1/immunology , Humans , Polyphosphates/chemistry , Polyphosphates/metabolism , SAM Domain and HD Domain-Containing Protein 1/genetics , Virus Replication
6.
PLoS One ; 11(8): e0160251, 2016.
Article in English | MEDLINE | ID: mdl-27505169

ABSTRACT

HIV controllers (HICs), rare HIV-1 infected individuals able to control viral replication without antiretroviral therapy, are characterized by an efficient polyfunctional and cytolytic HIV-specific CD8+ T cell response. The mechanisms underlying the induction and maintenance of such response in many HICs despite controlled viremia are not clear. Dendritic cells play a crucial role in the generation and reactivation of T cell responses but scarce information is available on those cells in HICs. We found that monocyte derived dendritic cells (MDDCs) from HICs are less permissive to HIV-1 infection than cells from healthy donors. In contrast MDDCs from HICs are particularly efficient at capturing HIV-1 particles when compared to cells from healthy donors or HIV-1 patients with suppressed viral load on antiretroviral treatment. MDDCs from HICs expressed on their surface high levels of syndecan-3, DC-SIGN and MMR, which could cooperate to facilitate HIV-1 capture. The combination of low susceptibility to HIV-1 infection but enhanced capacity to capture particles might allow MDDCs from HICs to preserve their function from the deleterious effect of infection while facilitating induction of HIV-specific CD8+ T cells by cross-presentation in a context of low viremia.


Subject(s)
Dendritic Cells/immunology , Dendritic Cells/virology , HIV Infections/immunology , HIV-1/physiology , Antigens, Viral/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/cytology , Dendritic Cells/metabolism , Disease Susceptibility , Gene Expression Regulation , Humans , Lectins, C-Type/metabolism , Syndecan-3/metabolism , Virus Replication
7.
J Immunol ; 197(7): 2787-95, 2016 10 01.
Article in English | MEDLINE | ID: mdl-27566819

ABSTRACT

Compared with HIV-1, HIV-2 infection is characterized by a larger proportion of slow or nonprogressors. A better understanding of HIV-2 pathogenesis should open new therapeutic avenues to establish control of HIV-1 replication in infected patients. In this study, we studied the production of CD8(+) T cells and their capacity for viral control in HIV-2 controllers from the French ANRS CO5 HIV-2 cohort. HIV-2 controllers display a robust capacity to support long-term renewal of the CD8(+) T cell compartment by preserving immune resources, including hematopoietic progenitors and thymic activity, which could contribute to the long-term maintenance of the CD8(+) T cell response and the avoidance of premature immune aging. Our data support the presence of HIV-2 Gag-specific CD8(+) T cells that display an early memory differentiation phenotype and robust effector potential in HIV-2 controllers. Accordingly, to our knowledge, we show for the first time that HIV-2 controllers possess CD8(+) T cells that show an unusually strong capacity to suppress HIV-2 infection in autologous CD4(+) T cells ex vivo, an ability that likely depends on the preservation of host immune resources. This effective and durable antiviral response probably participates in a virtuous circle, during which controlled viral replication permits the preservation of potent immune functions, thus preventing HIV-2 disease progression.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV Infections/virology , HIV-2/immunology , Lymphopoiesis/immunology , Adult , Aged , Female , HIV Infections/diagnosis , Humans , Male , Middle Aged
8.
J Virol ; 90(13): 6148-6158, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27122576

ABSTRACT

UNLABELLED: HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4(+) T cells and with less efficient virion production ex vivo We also found that a potent HIV-specific CD8(+) T cell response was present only in those HICs whose CD4(+) T cells produced virus ex vivo Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8(+) T cell response to counteract efficient viral reactivation events. IMPORTANCE: There is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4(+) T cells in vitro were the most difficult were those with diminished CD8(+) T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.


Subject(s)
CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , HIV Infections/virology , HIV-1/physiology , Virus Activation , Adult , Aged , Anti-HIV Agents/therapeutic use , Female , HIV Infections/drug therapy , HIV-1/growth & development , HIV-1/isolation & purification , Humans , Male , Middle Aged , RNA, Viral/blood , Virus Latency , Virus Replication
9.
J Virol ; 89(7): 3542-56, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25589645

ABSTRACT

UNLABELLED: The spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8(+) T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8(+) T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8(+) T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8(+) T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8(+) T cells that lacked efficient SIV suppression capacity ex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4(+) T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8(+) cell depletion and inducible SIV replication from its CD4(+) T cells in vitro. Altogether, our results suggest that CD8(+) T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control. IMPORTANCE: Spontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8(+) T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8(+) T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8(+) cells induced a rise in the viral load. However, viremia was correlated with CD4(+) T-cell activation subsequent to CD8(+) cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8(+) T cells. Our results suggest that CD8(+) T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/immunology , Animals , Leukocyte Reduction Procedures , Macaca fascicularis , Survivors , Viral Load
10.
J Infect Dis ; 212(1): 44-56, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25583169

ABSTRACT

Early on in human immunodeficiency virus (HIV) type 1 infection, gut T-helper (Th) 17 cells are massively depleted leading eventually to compromised intestinal barrier function and excessive immune activation. In contrast, the functional Th17 cell compartment of the gut is well-maintained in nonpathogenic simian immunodeficiency virus infection as well as HIV-1 long-term nonprogressors. Here, we show that dendritic cells (DCs) loaded with HIV-1 bearing high surface complement levels after incubation in plasma from HIV-infected individuals secreted significantly higher concentrations of Th17-polarizing cytokines than DCs exposed to nonopsonized HIV-1. The enhanced Th17-polarizing capacity of in vitro-generated and BDCA-1(+) DCs directly isolated from blood was linked to activation of ERK. In addition, C3a produced from DCs exposed to complement-opsonized HIV was associated with the higher Th17 polarization. Our in vitro and ex vivo data, therefore, indicate that complement opsonization of HIV-1 strengthens DC-mediated antiviral immune functions by simultaneously triggering Th17 expansion and intrinsic C3 formation via DC activation.


Subject(s)
CD11b Antigen/analysis , CD11c Antigen/analysis , Cell Differentiation , Complement System Proteins/immunology , Dendritic Cells/immunology , HIV-1/immunology , Th17 Cells/physiology , Adult , Female , Humans , Male , Middle Aged
11.
J Virol ; 88(20): 11861-71, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25100841

ABSTRACT

During HIV infection, increased CD57 expression among CD8(+) T cells has been associated with immune senescence and defective immune responses. Interestingly, CD57-expressing CD8(+) T cells exhibit a dual profile, being simultaneously highly cytotoxic (terminally differentiated effectors) and poorly proliferative (replicative senescent). Recent publications point toward a positive role of CD57-expressing CD8(+) T cell subsets, presumably due to their high cytolytic activity. We further investigated the phenotype of CD57-expressing CD8(+) T cells in healthy donors and during HIV infection combining CD57 expression to Eomesodermin (EOMES), a T box transcription factor which determines, coordinately with T-bet, effector and memory CD8(+) T cell differentiation. We defined in healthy donors two functionally distinct CD57-expressing CD8(+) T cell subsets exhibiting different levels of EOMES expression: EOMES(hi) CD57(+) and EOMES(int) CD57(+) CD8(+) T cells. EOMES(hi) CD57(+) cells exhibited low cytotoxic activity but preserved proliferative capacity and interleukin 7 (IL-7) receptor expression, whereas EOMES(int) CD57(+) cells exhibited obvious cytotoxic functions and a more terminally differentiated phenotype. We next performed a similar analysis in different contexts of HIV infection: primary infected patients, long-term viremic patients, aviremic patients treated with antiretroviral therapy, and HIV controllers; we demonstrated a higher percentage of CD57-expressing cells in all HIV-infected patients regardless of virological status. When heterogeneity in EOMES expression among CD57 cells was taken into account, we detected significantly higher proportions of EOMES(hi) CD57(+) cells among HIV-specific and nonspecific CD8(+) T cells from HIV controllers than in aviremic antiretroviral-treated patients and viremic patients. Importantly, such a peculiar non-terminally differentiated EOMES(hi) CD57(+) phenotypic profile was associated with viral control. Importance: This study demonstrates that functional heterogeneity exists among CD57-expressing CD8 T cells, which include both terminally differentiated, highly cytotoxic EOMES(int) CD57(+) CD8(+) T cells and less differentiated EOMES(hi) CD57(+) CD8 T cells, which do not exhibit immediate cytotoxic functions but present high proliferative capacity. Interestingly, HIV controllers present a high proportion of EOMES(hi) CD57 cells among CD57-expressing HIV-specific CD8 T cells compared to both long-term viremic and aviremic antiretroviral therapy (ART)-treated patients, suggesting a beneficial role for this cell subset in viral control.


Subject(s)
CD57 Antigens/immunology , CD8-Positive T-Lymphocytes/virology , HIV Infections/virology , T-Box Domain Proteins/metabolism , Adult , HIV Infections/immunology , Humans , Middle Aged
12.
PLoS One ; 9(7): e101920, 2014.
Article in English | MEDLINE | ID: mdl-25000587

ABSTRACT

BACKGROUND: HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38-/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status. MATERIALS AND METHODS: We compared CD38-/HLA-DR+ CD8+ T cells with the classical CD38+/HLA-DR+ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated. RESULTS: Compared to CD38+/HLA-DR+ cells, CD38-/HLA-DR+ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134-462] vs 638 [307-747], P = 0.001), higher frequency of polyfunctional cells (15% [7%-33%] vs 21% [16%-43%], P = 0.0003), greater proliferative capacity (0-fold [0-2] vs 3-fold [2]-[11], P = 0.007), and higher cytotoxicity in vitro (7% [3%-11%] vs 13% [6%-22%], P = 0.02). The CD38-/HLA-DR+ profile was preferentially generated in response to low viral antigen concentrations. CONCLUSIONS: These data highlight the role of CD38-/HLA-DR+ HIV-specific CD8+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8+ subset may be important for vaccine strategies.


Subject(s)
ADP-ribosyl Cyclase 1/immunology , CD8-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV-1/immunology , HLA-DR Antigens/immunology , T-Lymphocytes, Cytotoxic/immunology , Adult , Antigens, CD/immunology , Case-Control Studies , Cells, Cultured , Female , Flow Cytometry , HIV Infections/prevention & control , HIV Infections/virology , Humans , Immunophenotyping , Lymphocyte Activation , Male , Middle Aged
14.
PLoS One ; 9(1): e85516, 2014.
Article in English | MEDLINE | ID: mdl-24465584

ABSTRACT

OBJECTIVE: HIV "elite controllers" (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs). METHODS: ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models. RESULTS: After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63√CD4/month), followed by +0.19√CD4/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm(3), the estimated mean CD4 T-cell gain during the first 12 months was 139/mm(3) in VIRs and 80/mm(3) in ECs (p = 0.048). CONCLUSIONS: cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients.


Subject(s)
Antiretroviral Therapy, Highly Active , HIV Infections/drug therapy , International Cooperation , Adult , CD4 Lymphocyte Count , Cohort Studies , Female , HIV Infections/immunology , Humans , Kinetics , Linear Models , Male , Middle Aged , Viremia/virology
15.
AIDS ; 28(4): 467-76, 2014 Feb 20.
Article in English | MEDLINE | ID: mdl-24378753

ABSTRACT

BACKGROUND: Although HIV controllers (HICs) achieve long-term control of viremia in the absence of antiretroviral therapy (ART), they display marked immune activation. The levels of inflammatory biomarkers in HICs and the biomarkers' relationships with immunologic and virologic status have yet to be fully characterized. DESIGN: A cohort study. METHODS: Plasma levels of seven biomarkers [tumor necrosis factor (TNF)α, interleukin (IL)6, IL10, interferon gamma-induced protein 10 (IP10), monocyte chemoattractant protein-1 (MCP1), soluble CD14 (sCD14), soluble CD163 (sCD163)] were compared in 70 HICs, 33 HIV-1-infected, treatment-naive noncontrollers (viremic patients), 30 ART-treated patients and 40 healthy donors. In HICs, we investigated the interplay between biomarkers, cell activation and the CD4⁺ T-cell count. RESULTS: HICs had higher levels of IP10, TNFα and sCD14 than healthy donors did (P < 0.01 for each). Also, TNFα and sCD14 levels of the HICs were similar to those measured in viremic and ART-treated patients. However, the levels of IL6 and IL10 were significantly lower in HICs than in viremic or ART-treated patients. In HICs, only IP10 levels differed significantly from those in both healthy donors and viremic patients, and were positively correlated with the expression of CD8⁺ and CD4⁺ T-cell activation markers. The IP10 levels of HICs were still elevated 12 and 24 months after the initial assay. Lastly, IP10 levels at enrollment were negatively correlated with the CD4⁺ T-cell count at enrollment and 12 months later. CONCLUSION: HICs display a number of inflammatory features associated with persistent T-cell immune activation.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Chemokine CXCL10/blood , Cytokines/blood , HIV Infections/immunology , HIV Infections/pathology , HIV Long-Term Survivors , Lymphocyte Activation , Adult , Biomarkers/blood , Cohort Studies , Disease Progression , Female , Humans , Male , Middle Aged
16.
J Virol ; 88(1): 176-87, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24131719

ABSTRACT

CD8(+) T cell responses are thought to play an important role during HIV infection, particularly in HIV controllers (HIC) in whom viral replication is spontaneously controlled without any treatment. We have demonstrated that CD8(+) T cells from these subjects are able to suppress viral replication in vitro. In parallel, HIV-specific CD8(+) responses were shown to be strong and of high quality, with proliferative abilities and cytotoxic capacities, in HIC. The HLA-B*57 allele, which is associated with a better clinical outcome in HIV infection, is overrepresented in HIC. However, we showed that these patients constitute a heterogeneous group that includes subjects who present weak suppression of viral replication in vitro and HIV-specific responses. We performed an extensive study of 101 HIC (49 HLA-B*57(+) and 52 HLA-B*57(-)) to determine the impact of HLA-B*57 on the HIV-specific CD8(+) response. The HLA-B*57-restricted response displayed better qualitative features, such as higher functional avidity, higher proliferation capacity, and a higher level of cytokine production, than responses not restricted by HLA-B*57. However, the highest frequencies of HIV-specific CD8(+) T cells were observed only in a subset of HLA-B*57(+) subjects. They were tightly associated with the ability to suppress viral replication in vitro. In contrast, the subset of HLA-B*57(+) subjects with a weak ability to suppress viral replication had significantly lower ultrasensitive viral loads than all the other groups of controllers. In conclusion, both HLA-B*57 and the amount of ultrasensitive viral load seem to play a role in HIV-specific CD8(+) T cell responses in HIC.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV/genetics , HLA-B Antigens/blood , RNA, Viral/blood , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , HIV/physiology , HIV Infections/virology , Humans , Male , Virus Replication
17.
Proc Natl Acad Sci U S A ; 110(42): E3997-4006, 2013 Oct 15.
Article in English | MEDLINE | ID: mdl-24082141

ABSTRACT

Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAM domain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/metabolism , Deoxyribonucleotides/biosynthesis , Gene Expression Regulation, Enzymologic , HIV Infections/metabolism , HIV-1/physiology , Macrophages/metabolism , Ribonucleotide Reductases/biosynthesis , Virus Replication/physiology , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p21/genetics , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , DNA, Viral/biosynthesis , DNA, Viral/genetics , Deoxyribonucleotides/genetics , Down-Regulation/genetics , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/metabolism , HIV Infections/therapy , HIV Infections/virology , Macrophages/virology , Monomeric GTP-Binding Proteins/genetics , Monomeric GTP-Binding Proteins/metabolism , Ribonucleotide Reductases/genetics , SAM Domain and HD Domain-Containing Protein 1 , Simian Immunodeficiency Virus/physiology , Transcription, Genetic/genetics
18.
Immunol Rev ; 254(1): 281-94, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23772626

ABSTRACT

Less than 0.5% of human immunodeficiency virus-1 (HIV-1)-infected patients maintain viral load below the threshold of detection by conventional assays for many years without antiretroviral therapy. These patients are known as HIV controllers (HICs) and offer a unique opportunity to explore and unravel efficient mechanisms of defense against HIV. An intense research effort has led to identifying viral and host factors that contribute to the control of viral replication. Although the host factors appear to be the primary determinants for HIV control, different genomic, transcriptomic, and immunological profiles have been described in HICs. This supports the existence of different mechanisms of control. We review here the most significant data in the field, including our own work, in the light of a crucial question: whether the ability to achieve and maintain the control of HIV replication is linked to genetic or immunological features specific to HIC or can be induced by vaccine or therapeutic approaches in the general population.


Subject(s)
HIV Infections/genetics , HIV Infections/immunology , HIV-1/physiology , Adaptive Immunity , Animals , HIV Infections/drug therapy , HIV Infections/virology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate
19.
PLoS One ; 8(3): e59767, 2013.
Article in English | MEDLINE | ID: mdl-23555774

ABSTRACT

The strong CD8+ T-cell-mediated HIV-1-suppressive capacity found in a minority of HIV-infected patients in chronic infection is associated with spontaneous control of viremia. However, it is still unclear whether such capacities were also present earlier in the CD8+ T cells from non controller patients and then lost as a consequence of uncontrolled viral replication. We studied 50 patients with primary HIV-1-infection to determine whether strong CD8+ T-cell-mediated HIV suppression is more often observed at that time. Despite high frequencies of polyfunctional HIV-specific CD8+ T-cells and a strong CD4+ T-helper response, CD8+ T-cells from 48 patients lacked strong HIV-suppressive capacities ex vivo. This indicates that the superior HIV-suppressive capacity of CD8+ T-cells from HIV controllers is not a general characteristic of the HIV-specific CD8+ T cell response in primary HIV infection.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , HIV Infections/immunology , HIV Infections/virology , Acute Disease , Adult , CD4-Positive T-Lymphocytes/cytology , Cells, Cultured , Cytokines/metabolism , Disease Progression , Female , HIV-1/physiology , Humans , Interleukin-2/metabolism , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Time Factors , Viral Load , Virus Replication
20.
PLoS Pathog ; 9(3): e1003211, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23516360

ABSTRACT

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.


Subject(s)
Anti-HIV Agents/administration & dosage , HIV Infections/prevention & control , HIV-1/drug effects , Alleles , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cohort Studies , Drug Therapy, Combination , Female , Follow-Up Studies , HIV Infections/drug therapy , HIV Infections/virology , HIV Seropositivity , HIV-1/physiology , Histocompatibility Testing , Humans , Male , Middle Aged , RNA, Viral/genetics , Viral Load , Viremia/prevention & control , Virus Replication
SELECTION OF CITATIONS
SEARCH DETAIL
...