HIV-specific CD8 T-cell Research Articles

GITR activation ex vivo impairs CD8 T cell function in people with HIV on antiretroviral therapy

Glucocorticoid-induced tumor necrosis factor related protein (GITR) is a co-stimulatory immune checkpoint molecule constitutively expressed on regulatory Tcells (Tregs) and on activated T conventional cells (Tconv). In blood collected from PWH on suppressive ART, GITR expression was reduced in multiple activated CD4 and CD8 Tcell subsets but was increased in Tregs. HIV specific CD8 Tcells expressed higher levels of GITR and programmed cell death protein 1 (PD-1) compared to total CD8 Tcells. Following stimulation with HIV peptides and GITR-ligand (L), we demonstrated a significant decrease in killing by HIV specific CD8 Tcells and an increased exhausted profile. Tcell receptor co-stimulation with GITR-L abrogated Treg suppression and induced expansion of CD4 Tconv. We conclude that GITR activation is an additional factor contributing to an impaired HIV immune response in PWH on ART and that GITR agonist antibodies should not be pursued for HIV cure strategies.

OP 4.3 – 00112 Leaky reservoirs are associated with HIV-specific cd4 and CD8 T-cell responses

OP 4.3 – 00112 Leaky reservoirs are associated with HIV-specific cd4 and CD8 T-cell responses

Hiv Specific T Cells Generated from HIV Naive Adult and Cord Blood Donors Target a Range of Novel Viral Epitopes: Implications for a Cure Strategy after Allogeneic HSCT and CBT

Adoptive T cell therapy has been successful in boosting viral-specific immunity post-HSCT, preventing viral rebound of CMV and EBV. However, the therapeutic use of T cells to boost HIV-specific T cell immunity in HIV+ patients has been met with limited success. Despite multiple attempts to eradicate HIV with allogeneic HSCT, there is only one case of functional HIV cure post-HSCT, the Berlin Patient. Hence, we hypothesized that broadly HIV-specific CD8 and CD4 T-cells (HXTCs) could be expanded from patients on ARVs, as well as HIV negative adult (dHXTCs) and cord blood donors (cbHXTCs), employing a non-HLA restricted approach for the treatment of HIV+ individuals after autologous or allogeneic HSCT.We have expanded autologous HXTCs from HIV+ subjects under NCT02208167. To extend this approach to the allogeneic HSCT setting, we generated dHXTCs from HIV naive adults (n=8) and cbHXTCs from cord blood donors (n=8). IFN-gamma ELISPOT showed dHXTCs were specific against Gag (mean=331.25 SFC/105cells) and Nef (mean=242.63) versus irrelevant antigen (mean=13 SFC) (n=8). Similarly, we are able to produce cbHXTCs (n=8) that showed specificity to Gag (mean=103.252 SFC/105cells), Nef (mean=109.43), or Pol (mean=130.56), (p<0.0001 compared to controls) in IFN-gamma ELISPOT. dHXTC products displayed polyfunctionality, producing proinflammatory TNFα, IL2, IL6, IL8, and perforin responses (p<0.05) to HIV stimulation. Importantly, dHXTCs (p=0.0004) and cbHXTCs (p=0.0003) were able to suppress HIV replication compared with nonspecific CD8+ T cells when co-cultured with autologous CD4+ T cells infected with HIV SF162 at an Effector-to-Target ratio of 20 to 1. Exhaustion marker analysis of cbHXTCs products revealed minimal expression of PD1, TIM3, LAG3, KLRG1, and CD57 (n=3). Epitope mapping revealed that dHXTC and cbHXTC products contained T cells recognizing unique epitopes not typically identified in HIV positive individuals, which may be critical in overcoming viral immune escape post-HSCT.In summary, HIV-specific T cells can be expanded from HIV positive and HIV negative donors for clinical use. Focusing on donors with HLA types that are associated with well characterized HIV responses (HLA A02) or associated with delayed progression to AIDS (HLA B27, B51, B57) may allow us to identify HLA restricted epitopes critical for the successful development of a potent HIV-specific T cell therapeutic. Hence, the administration of HXTCs derived from virus naive donors could offer a unique curative strategy post-allogeneic HSCT and cord blood transplant. [Display omitted] DisclosuresBollard:Torque: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Neximmune: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

Neutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

Evaluation of HIV-specific T-cell responses in HIV-infected older patients with controlled viremia on long-term antiretroviral therapy

HIV-infected older individuals may have a diminished immune response because of exhaustion/immune aging of T-cells. Therefore, we have investigated HIV-specific CD4 and CD8 T-cell responses in 100 HIV-infected patients (HIV+) who have aged on long-term antiretroviral therapy (ART) and achieved controlled viremia (mostly undetectable viral load; 92 patients with <20 to <40 HIV RNA copies/mL and 8 <60 to <100) and improved CD4 T-cell counts. We show that the median frequencies of HIV-specific CD4+ and CD8+ IFN-γ T-cells were higher in HIV+ than uninfected individuals (HIV-), including increasing levels of IFN-γproduced by CD4+ T-cells and decreasing levels by CD8+ T-cells with increasing CD4 T-cell counts in HIV+. No correlation was found between T-cell responses and varying levels of undetectable viremia. HIV-specific TNF-α made by CD8+ T-cells was higher in HIV+ than HIV-, including decreasing levels with increasing CD4 T-cell counts in HIV+. Furthermore, the CD8+ T-cell mediators, CD107a and Granzyme-B, were higher in HIV+ than HIV-, and decreased with increasing CD4 T-cell counts in HIV+. Remarkably, HIV-specific CD8 T-cells produced decreasing levels of IFN-γwith increasing age of HIV+, including decreased levels of CD107a and Granzyme-B in older HIV+. However, HIV-specific CD8+ T-cells produced increasing levels of TNF-α with increasing age of the HIV+, suggesting continued inflammation. In conclusion, HIV+ with controlled viremia on long-term ART and with higher CD4 T-cell counts showed reduced HIV-specific CD8 T-cell responses as compared to those with lower CD4 T-cell counts, and older HIV+ exhibited decreasing levels of CD8 T-cell responses with increasing age.

Evaluation of HIV-Specific T-Cell Responses in HIV-Infected Aging Patients with Controlled Viremia on Long-term Antiretroviral Therapy

Abstract While long-term antiretroviral therapy (ART) has helped many human immunodeficiency virus type 1 (HIV-1) infected aging patients to achieve controlled viremia and restored CD4 T-cell counts, the role of HIV-specific T-cell responses in these patients is not clearly understood. We have investigated HIV-specific CD4 and CD8 T-cell responses in 100 HIV-infected patients (HIV+) who have aged on long-term antiretroviral therapy (ART) with controlled viremia and restored CD4 T-cell counts. We show the median circulating HIV-specific CD4+ and CD8+IFN-γ T-cells in HIV+ were higher than uninfected controls (HIV−), including increased levels of HIV-specific CD4+IFN-γ T-cells and decreased levels of CD8+IFN-γ T-cells with increasing CD4T-cell counts in HIV+. In addition, HIV-specific CD8+TNF-α T-cells were higher in HIV+ than HIV−, including decreasing levels were seen with increasing CD4T-cell counts of HIV+. Furthermore, the CD8+ T-cell mediators, Granzyme B and CD107a, were higher in HIV+ than HIV−, however these mediators decreased with increasing CD4 T-cell counts in HIV+. More importantly, HIV-specific CD4+ and CD8+ T-cells produced higher levels of IFN-γ and CD8+ T-cells TNF-α, Granzyme B and CD107a with increasing age of HIV+ probably to counter residual HIV and reduced immunity in older individuals. In conclusion, while HIV-infected patients with controlled viremia and improved CD4 T-cell counts showed reduced CD8 T-cell responses, the CD8 T-cell responses were higher in HIV+ with lower CD4 T-cell counts as well as in HIV+ patients with increasing age.

Circulating CXCR5-Expressing CD8+ T-Cells Are Major Producers of IL-21 and Associate With Limited HIV Replication.

Despite advances made with the highly active antiretroviral therapy (HAART) in the control of the HIV 1 infection, a cure has not been achieved because of the persistence of viral reservoirs. The major HIV reservoirs remain in the lymphoid follicles because of, among other factors, the partial absence of CD8 T-cells in these structures. Recently, lymphoid follicle-confined and circulating CD8 T-cells expressing the C-X-C chemokine receptor type 5 (CXCR5) were described, possessing antiviral mechanisms that could help to control HIV replication. By flow cytometry, we characterized the phenotype and function of circulating CXCR5-expressing CD8 T-cells in HIV-infected patients with natural or HAART-induced control of HIV replication. Circulating CXCR5-expressing CD8 T-cells exhibited low or null expression of the C-C chemokine receptor type 7 (CCR7) and had a transitional memory phenotype. Particular redistributions of CXCR5-expressing CD8 T-cells were found in HIV-infected patients, and they were partially restored by HAART. The frequency of CXCR5CCR7 CD8 T-cells was higher in spontaneous HIV controllers and negatively correlated with plasma HIV RNA levels. Total and HIV-specific CXCR5 CD8 T-cells were major producers of interleukin-21, and this function was positively associated with their interferon-γ production. Circulating CXCR5-expressing CD8 T-cells are associated with low-level HIV replication; these cells could be novel correlates of protection, and potentially useful in the eradication of HIV reservoirs.

HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India.

Background: Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective: This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods: HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results: Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion: LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

CD4 T-Cell Responses in Primary HIV Infection: Interrelationship with Immune Activation and Virus Burden

Early events during primary HIV infection (PHI) are thought to influence disease outcome. Although a growing body of evidence suggests a beneficial role of HIV-specific CD4 help in HIV infection, it is unclear how early viral replication, systemic immune activation, and antiretroviral therapy (ART) may shape CD4 T-cell responses during PHI, and whether HIV-specific CD4 responses contribute to the high immune activation observed in PHI. Twenty-seven patients with early PHI were included in a prospective longitudinal study and 12 of them received ART after enrollment. Fresh peripheral blood mononuclear cells were used for measurement of ex vivo T-cell activation and of cytokine-producing CD4 T-cells following stimulation with PMA/ionomycin or HIV-1-gag-p24 antigen. Patients were segregated based on CD8 T-cell activation level (i.e., % HLA-DR+CD38+ CD8 T-cells) at baseline (BL). Patients with lower immune activation exhibited higher frequency of bulk CD4 T-cells producing IFN-γ or IL-17 and higher effector-to-regulatory cell ratios. No differences were found in HIV-specific CD4 T-cell frequencies. In contrast, segregation of patients based on plasma viral load (pVL) revealed that patients with higher pVL showed higher cytokine-producing HIV-specific CD4 responses. Of note, the frequency of IFN-γ+ HIV-specific CD4 T cells significantly diminished between BL and month 6 only in ART-treated patients. However, early treatment initiation was associated with better maintenance of HIV-specific IFN-γ+ CD4 T-cells. These data suggest that HIV-specific CD4 responses do not fuel systemic T-cell activation and are driven by viral replication but not able to contribute to its control in the early phase of infection. Moreover, our data also suggest a benefit of early treatment for the maintenance of HIV-specific CD4 T-cell help.

A piecewise model of virus-immune system with two thresholds

The combined antiretroviral therapy with interleukin (IL)-2 treatment may not be enough to preclude exceptionally high growth of HIV virus nor rebuilt the HIV-specific CD4 or CD8 T-cell proliferative immune response for management of HIV infected patients. Whether extra inclusion of immune therapy can induce the HIV-specific immune response and control HIV replication remains challenging. Here a piecewise virus-immune model with two thresholds is proposed to represent the HIV-1 RNA and effector cell-guided therapy strategies. We first analyze the dynamics of the virus-immune system with effector cell-guided immune therapy only and prove that there exists a critical level of the intensity of immune therapy determining whether the HIV-1 RAN virus loads can be controlled below a relative low level. Our analysis of the global dynamics of the proposed model shows that the pseudo-equilibrium can be globally stable or locally bistable with order 1 periodic solution or bistable with the virus-free periodic solution under various appropriate conditions. This indicates that HIV viral loads can either be eradicated or stabilize at a previously given level or go to infinity (corresponding to the effector cells oscillating), depending on the threshold levels and the initial HIV virus loads and effector cell counts. Comparing with the single threshold therapy strategy we obtain that with two thresholds therapy strategies either virus can be eradicated or the controllable region, where HIV viral loads can be maintained below a certain value, can be enlarged.

Lessons from acute HIV infection.

Purpose of reviewUnderstanding the characteristics of transmission during acute HIV infection (AHI) may inform targets for vaccine-induced immune interdiction. Individuals treated in AHI with a small HIV reservoir size may be ideal candidates for therapeutic HIV vaccines aiming for HIV remission (i.e. viremic control after treatment interruption).Recent findingsThe AHI period is brief and peak viremia predicts a viral set point that occurs 4–5 weeks following infection. Robust HIV-specific CD8+ T-cell responses lower viral set points. Phylogenetic analyses of founder viruses demonstrated unique bottleneck selections and specific genetic signatures to optimize for high-fitness variants and successful transmission events. HIV clades, route of transmission and the presence of minor variants may affect vaccine protection. Antiretroviral treatment in AHI results in smaller HIV reservoir size, better CD4+ T-cell recovery and fewer virus escapes.SummaryThe knowledge of untreated and treated AHI informs the development of vaccines, in that preventive vaccines will require broad coverage for multiple clades and antigenic variants associated with unique bottleneck selections. Vaccines that help the host to control viremia could minimize onward transmission. Therapeutic HIV vaccines aimed at HIV remission should be studied in early-treated individuals who have few or no viral escape mutants and a more preserved immune system.

Balance between activation and regulation of HIV-specific CD8+ T-cell response after modified vaccinia Ankara B therapeutic vaccination.

The causes of HIV-vaccines failure are poorly understood. Therapeutic vaccination with modified vaccinia Ankara (MVA)-B in HIV-1-infected individuals did not control the virus upon analytical treatment interruption (ATI). We investigated whether the functional characteristics of HIV-specific CD8 T-cell responses stimulated by this vaccine, and the level of exhaustion of these cells might explain these results. Twenty-one HIV-1 chronically infected patients on combination antiretroviral therapy, included in the therapeutic vaccine trial RISVAC03, were studied: 13 immunized and eight controls. Functional characteristics, cytotoxic potential and exhaustion of HIV-specific CD8 T cells, were evaluated by polychromatic flow cytometry. Differences between groups were tested using nonparametric tests. MVA-B vaccine induced an increase in HIV-specific CD8 T-cell response, but also increased their levels of exhaustion. At week 18 (following three immunizations) the level of response increased with respect to baseline (P = 0.02). A significant increase at weeks 18 and 24 (ATI) in granzyme B content was also observed. Interestingly, an increase in expression of exhaustion markers was found at weeks 18 (P = 0.006) and 24 (P = 0.01). However, there was no significant change in the functional profile of vaccine-induced CD8 cells. At week 36, in parallel to the rebound of plasma viremia after 12 weeks ATI, a significant increase in the level of CD8 response, in granzyme B content and in exhaustion markers expression, was observed in both groups. We show that therapeutic vaccination with MVA-B tilts the balance between activation and regulation of the response of HIV-specific CD8 T cells towards regulation, which impacts on the viral rebound after ATI.

Recombinant influenza virus expressing HIV-1 p24 capsid protein induces mucosal HIV-specific CD8 T-cell responses

Influenza viruses are promising mucosal vaccine vectors for HIV but their use has been limited by difficulties in engineering the expression of large amounts of foreign protein. We developed recombinant influenza viruses incorporating the HIV-1 p24 gag capsid into the NS-segment of PR8 (H1N1) and X31 (H3N2) influenza viruses with the use of multiple 2A ribosomal skip sequences. Despite the insertion of a sizable HIV-1 gene into the influenza genome, recombinant viruses were readily rescued to high titers. Intracellular expression of p24 capsid was confirmed by in vitro infection assays. The recombinant influenza viruses were subsequently tested as mucosal vaccines in BALB/c mice. Recombinant viruses were attenuated and safe in immunized mice. Systemic and mucosal HIV-specific CD8 T-cell responses were elicited in mice that were immunized via intranasal route with a prime-boost regimen. Isolated HIV-specific CD8 T-cells displayed polyfunctional cytokine and degranulation profiles. Mice boosted via intravaginal route induced recall responses from the distal lung mucosa and developed heightened HIV-specific CD8 T-cell responses in the vaginal mucosa. These findings demonstrate the potential utility of recombinant influenza viruses as vaccines for mucosal immunity against HIV-1 infection.

HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report

Durable HIV-1 remission after interruption of combined antiretroviral therapy (ART) has been reported in some adults who started treatment during primary infection; however, whether long-term remission in vertically infected children is possible was unknown. We report a case of a young adult perinatally infected with HIV-1 with viral remission despite long-term treatment interruption. The patient was identified in the ANRS EPF-CO10 paediatric cohort among 100 children infected with HIV perinatally who started ART before 6 months of age. HIV RNA viral load and CD4 cell counts were monitored from birth. Ultrasensitive HIV RNA, peripheral blood mononuclear cell (PBMC)-associated HIV DNA, HIV-specific T-cell responses (ie, production of cytokines and capacity to suppress HIV infection), reactivation of the CD4 cell reservoir (measured by p24 ELISA and HIV RNA in supernatants upon phytohaemagglutinin activation of purified CD4 cells), and plasma concentrations of antiretroviral drugs were assessed after 10 years of documented control off therapy. The infant was born in 1996 to a woman with uncontrolled HIV-1 viraemia and received zidovudine-based prophylaxis for 6 weeks. HIV RNA and DNA were not detected 3 days and 14 days after birth. HIV DNA was detected at 4 weeks of age. HIV RNA reached 2·17× 10(6) copies per mL at 3 months of age and ART was started. HIV RNA was undetectable 1 month later. ART was discontinued by the family at some point between 5·8 and 6·8 years of age. HIV RNA was undetectable at 6·8 years of age and ART was not resumed. HIV RNA has remained below 50 copies per mL and CD4 cell counts stable through to 18·6 years of age. After 11·5 years of control off treatment, HIV RNA was below 4 copies per mL and HIV DNA was 2·2 log10 copies per 10(6) PBMCs. The HLA genotype showed homozygosity at several loci (A*2301-, B*1503/4101, C*0210/0802, DRB1*1101-, and DQB1*0602-). HIV-specific CD8 T-cell responses and T-cell activation were weak. Findings from this case suggest that long-term HIV-1 remission is possible in perinatally infected children who receive treatment early, with characteristics similar to those reported in adult HIV post-treatment controllers. Further studies are needed to understand the mechanisms associated with HIV remission and whether early treatment of infected children might favour the conditions needed to achieve HIV control after treatment discontinuation. Agence de recherche ANRS (France Recherche Nord & Sud Sida-HIV Hépatites).

Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

CD8(+) Tcells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8(+) Tcell response, with limited bystander activation of non-HIV memory CD8(+) Tcells. HIV-specific CD8(+) Tcells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for Tcell survival. The rapidity to peak CD8(+) Tcell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8(+) Tcell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.

Characterization of functional antiviral CD8 T cell immune responses of HIV elite controllers by high dimensional phenotyping using mass cytometry (VIR6P.1169)

Abstract Elite controllers (EC) are individuals who control HIV infection without therapy through CD8 T cells. Chronic infections can lead to T cell exhaustion characterized by reduced proliferation and cytokine expression as well as upregulation of co-inhibitory molecules like PD-1. CD8 T cells from EC are more effective at killing HIV-infected targets than those from progressors. The underlying mechanism is not completely understood, but is affected by HLA type, T-cell receptor clonotype, viral epitopes targeted, and likely also by a complex regulatory network of activation and inhibition. However, the particular phenotype of activation and exhaustion markers associated with the increased killing of HIV-specific CD8 T cells from EC has remained unclear. To elucidate these regulatory networks, we performed high-dimensional phenotyping of HIV-specific CD8 T cells using mass cytometry (CyTOF), a cutting edge technology combining flow cytometry and mass spectrometry that enables analysis of up to 40 markers with minimal signal overlap. We established and validated a CyTOF panel of 33 markers to identify up to 6 HIV-specific CD8 T-cell subsets using tetramer technology and characterize memory, activation and exhaustion status of those cells. Use of our panel enables the in-depth characterization of HIV-specific CD8 T cells at a level of unprecedented granularity and may reveal signatures of activation and exhaustion networks that underlie the enhanced lytic capacity of these cells in EC.

Innate activation of MDC and NK cells in high-risk HIV-1-exposed seronegative IV-drug users who share needles when compared with low-risk nonsharing IV-drug user controls.

Previous studies have described increased innate immune activation in HIV-1-exposed seronegative intravenous drug users (HESN-IDU), but have not addressed the independent role of injected drugs and/or repeated injections in driving immune activation. In this study, we investigated innate [natural killer (NK) cells and dendritic cells] and adaptive (HIV-specific antibody and CD8 T cell) immune parameters among a high-risk cohort of needle-sharing HESN-IDU subjects and compared them with low-risk nonsharing IDU subjects (NS-IDU) and non-drug-user controls. We observed that HIV-specific antibody and CD8 T-cell responses were not detected in HESN-IDU subjects, yet innate immune cell activation was found to be significantly increased on NK cells (CD69 and CD107a upregulation) and myeloid dendritic cells (CD40 and CD83 upregulation) when compared with NS-IDU subjects or non-drug-user controls (P < 0.01 and P < 0.05, respectively). HESN-IDU subjects maintained strong NK-cell CD107a degranulation and cytokine (IFN-gamma, TNF-alpha, and MIP-1 beta) production after target cell incubation suggesting that constitutive innate activation does not induce functional exhaustion of innate cells in HESN-IDU subjects. NK activation in HESN-IDU subjects was independent of drug use patterns but was durable over time and correlated with plasma levels of IP-10 by Luminex analysis (ρ = 0.5073, P = 0.0059, n = 28). Our results indicate that heightened innate immune cell activation in HESN-IDU subjects is not the result of the IV drugs and repeated injection practice itself, but to repeated exposure to factors intrinsic to sharing needles (ie, exposure to pathogens or heterologous cells among donor blood).

Broad and persistent Gag-specific CD8+ T-cell responses are associated with viral control but rarely drive viral escape during primary HIV-1 infection.

We characterized protein-specific CD8 T-cell immunodominance patterns during the first year of HIV-1 infection, and their impact on viral evolution and immune control. We analyzed CD8 T-cell responses to the full HIV-1 proteome during the first year of infection in 18 antiretroviral-naïve individuals with acute HIV-1 subtype C infection, all identified prior to seroconversion. Ex-vivo and cultured interferon-γ ELISPOT assays were performed and viruses from plasma were sequenced within defined CTL Gag epitopes. Nef-specific CD8 T-cell responses were dominant during the first 4 weeks after infection and made up 40% of the total responses at this time; yet, by 1 year, responses against this region had declined and Gag responses made up to 47% of all T-cell responses measured. An inverse correlation between the breadth of Gag-specific responses and viral load set point was evident at 26 weeks after infection (P = 0.0081, r = -0.60) and beyond. An inverse correlation between the number of persistent responses targeting Gag and viral set point was also identified (P = 0.01, r = -0.58). Gag-specific responses detectable by the cultured ELISPOT assay correlated negatively with viral load set point (P = 0.0013, r = -0.91). Sequence evolution in targeted and nontargeted Gag epitopes in this cohort was infrequent. These data underscore the importance of HIV-specific CD8 T-cell responses, particularly to the Gag protein, in the maintenance of low viral load levels during primary infection, and show that these responses are initially poorly elicited by natural infection. These data have implications for vaccine design strategies.

Activation-induced cell death drives profound lung CD4(+) T-cell depletion in HIV-associated chronic obstructive pulmonary disease.

As overall survival improves, individuals with HIV infection become susceptible to other chronic diseases, including accelerated chronic obstructive pulmonary disease (COPD). To determine whether individuals with HIV-associated COPD exhibit dysregulated lung mucosal T-cell immunity compared with control subjects. Using flow cytometry, we evaluated peripheral blood and lung mucosal T-cell immunity in 14 HIV(+)COPD(+), 13 HIV(+)COPD(-), and 7 HIV(-)COPD(+) individuals. HIV(+)COPD(+) individuals demonstrated profound CD4(+) T-cell depletion with reduced CD4/CD8 T-cell ratios in bronchoalveolar lavage-derived lung mononuclear cells, not observed in peripheral blood mononuclear cells, and diminished CD4(+) T cell absolute numbers, compared with control subjects. Furthermore, HIV(+)COPD(+) individuals demonstrated decreased pulmonary HIV-specific and staphylococcal enterotoxin B-reactive CD4(+) memory responses, including loss of multifunctionality, compared with HIV(+)COPD(-) control subjects. In contrast, lung mucosal HIV-specific CD8(+) T-cell responses were preserved. Lung CD4(+) T cells from HIV(+)COPD(+) individuals expressed increased surface Fas death receptor (CD95) and programmed death-1, but similar bronchoalveolar lavage viral loads as control subjects. However, programmed death-1 expression inversely correlated with HIV-specific lung CD4(+)IFN-γ(+) T-cell responses, suggesting functional exhaustion. Moreover, lung CD4(+) T cells from HIV(+)COPD(+) patients demonstrated increased basal and HIV antigen-induced expression of the early apoptosis marker annexin V compared with control subjects, which was significantly attenuated with anti-Fas blockade. Lastly, lung mucosal, but not blood, CD4(+)/CD8(+) ratios from HIV(+) patients significantly correlated with the FEV1, but not in HIV(-)COPD(+) patients. Together, our results provide evidence for profound lung mucosal CD4(+) T-cell depletion via a Fas-dependent activation-induced cell death mechanism, along with impaired HIV-specific CD4(+) immunity as immunologic features of HIV-associated COPD.

Differences in Immunodominant Patterns and HLA-DRB1 Restriction Characteristics in HIV-specific CD4 T-cell Responses between Clade B and C Infection

AIDS Research and Human RetrovirusesVol. 30, No. S1 T-Cell (CD4 & CD8) ResponsesDifferences in Immunodominant Patterns and HLA-DRB1 Restriction Characteristics in HIV-specific CD4 T-cell Responses between Clade B and C InfectionFaatima Laher, Srinika Ranasinghe, Filippos Porichis, Isaiah Davis, Orestes Mavrothalassitis, Nasreen Ismail, Nikoshia Mewalal, Sannie Mahungela, Bruce D. Walker, Thumbi Ndung'u, and Zaza M. NdhlovuFaatima LaherHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South AfricaSearch for more papers by this author, Srinika RanasingheRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesSearch for more papers by this author, Filippos PorichisRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesSearch for more papers by this author, Isaiah DavisRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesSearch for more papers by this author, Orestes MavrothalassitisRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesSearch for more papers by this author, Nasreen IsmailHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South AfricaSearch for more papers by this author, Nikoshia MewalalHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South AfricaSearch for more papers by this author, Sannie MahungelaHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South AfricaSearch for more papers by this author, Bruce D. WalkerRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesHoward Hughes Medical Institute (HHMI), Chevy Chase, MD, United StatesSearch for more papers by this author, Thumbi Ndung'uHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South AfricaRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesSearch for more papers by this author, and Zaza M. NdhlovuHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South AfricaRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5375.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Differences in Immunodominant Patterns and HLA-DRB1 Restriction Characteristics in HIV-specific CD4 T-cell Responses between Clade B and C Infection." AIDS Research and Human Retroviruses, 30(S1), p. A177FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Faatima Laher, Srinika Ranasinghe, Filippos Porichis, Isaiah Davis, Orestes Mavrothalassitis, Nasreen Ismail, Nikoshia Mewalal, Sannie Mahungela, Bruce D. Walker, Thumbi Ndung'u, and Zaza M. Ndhlovu.Differences in Immunodominant Patterns and HLA-DRB1 Restriction Characteristics in HIV-specific CD4 T-cell Responses between Clade B and C Infection.AIDS Research and Human Retroviruses.Oct 2014.A177-A177.http://doi.org/10.1089/aid.2014.5375.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download