HIV-specific T-cell Research Articles

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.

How can Improve DNA Vaccine Modalities as a Therapeutic Approach against HIV Infections?

The recent studies have focused on the improvement of effective prophylactic and therapeutic approaches to combat persistent viral infections. Several therapeutic vaccine strategies have already used such as live-attenuated microbes, viral vectors and dendritic cell-based vaccines led to suppress and/or clear infections. Among them, improved DNA vaccines have emerged as a promising candidate for treatment of infectious diseases especially HIV infections. These vaccines have the advantages of safety, low cost of production, ease of use due to their stability in room temperature as well as ability to elicit efficient immune responses. Some strategies have been considered to improve immune responses stimulated by DNA vaccines, e.g., genetic optimization of plasmid DNA constructs encoding antigens, in vivo efficient DNA delivery systems, co-delivery with molecular adjuvants as well as the development of potent heterologous prime-boost regimens. DNA vaccines have an intrinsic bias towards generating cellular immunity against intracellular pathogens. By manipulating the DNA formulation and delivery, effective antibody responses can be also induced. For instance, the studies showed that the immunized monkeys with DNA vaccine developed HIVspecific T-cell immune responses that persisted for months. It is important to develop the potency of this modality in the clinic. In this review, the authors will focus on the recent improvements to enhance DNA vaccine potency in combating persistent HIV virus infections

Absence of Detectible HIV-1 Viremia After Treatment Cessation in an Infant.

Until very recently, the only patient “cured” of HIV was the “Berlin patient,” an adult male treated for HIV-associated acute myeloid leukemia with stem cell transplantation from a donor who was intrinsically resistant to HIV. The donor carried homozygous mutations (delta32) in the chemokine receptor 5 gene, which is an essential co-receptor for HIV entry into most target cells. The present study reports on an infant who also may be cured with early, highly active antiretroviral therapy (ART) after documented perinatal infection.A 35-week gestational age infant was born by normal vaginal delivery to an HIV-infected woman who received no prenatal care and who was not taking ART. ART was initiated in the infant at 30 hours of age with zidovudine, lamivudine, and nevirapine. At 1 week of age, this regimen was adjusted to zidovudine, lamivudine, and ritonavir-boosted lopinavir. The infant remained on ART for 18 months and was then lost to follow-up until 23 months of age. ART has been discontinued and, because of results from subsequent studies, has not been restarted.Standard HIV polymerase chain reaction (PCR) assays and HIV antibody testing were used to diagnose and monitor the HIV-exposed infant. Peripheral blood mononuclear cell cultures were analyzed with PCR for virus DNA and with co-culture techniques for replication-competent virus. Lymphocyte subset analysis was conducted with standard flow cytometry, and HIV-specific T-cell responses were evaluated with intracellular cytokine generation assays.During the first month of life and while receiving ART, the infant had elevated quantitative HIV RNA PCR measurements that declined to undetectable levels and remained there. Subsequently, although proviral DNA was detected at the limits of the assay at 26 months of age, plasma viral RNA was undetectable, and replication-competent virus could not be cultured at age 24 months. HIV antibody assays were not detected in the infant at or after 24 months of age, when maternal antibody would not confound the assays, and HIV-specific T-cell responses were not detected at age 28 months. CD4+ T-cell counts remain normal throughout the study.Very early ART therapy in infants born at risk may abort HIV infection.In patients with established HIV infection, effective ART drives the virus to “undetectable” levels, usually defined as <20/copies of viral RNA/mL of plasma. However, viremia persists in such patients at very low levels and as DNA pro-virus in peripheral blood mononuclear cells. Was this infant cured of HIV? According to the Centers for Disease Control and Prevention definition, the infant was “infected”: 2 positive PCR test results on at least 2 different blood specimens. The data presented demonstrated that after unintended discontinuation of therapy, the infant remained free of replication-competent HIV from at least 12 months of age. As the authors conclude, “very early ART in infants may alter the establishment and long term persistence of HIV-infection.” But why might this happen in a newborn when it has not been demonstrated in older patients except under the unique circumstances of the Berlin patient? HIV persistence depends on the establishment of a reservoir of infected cells. Recent studies suggest that this condition involves a specific population of “central memory T cells.” Perhaps very early therapy aborts or inhibits establishment of this reservoir or perhaps these cells have not fully matured to be infected in newborns. In any case, the present report suggests that very early therapy may prevent establishment of HIV in high-risk infants, and certainly this possibility is being studied intensively.

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

Pre-exposure Prophylaxis Does Not Enhance HIV-specific T-cell Responses

AIDS Research and Human RetrovirusesVol. 30, No. S1 T-Cell (CD4 & CD8) ResponsesPre-exposure Prophylaxis Does Not Enhance HIV-specific T-cell ResponsesLaura Pattacini, Pamela M. Murnane, Jared M. Baeten, Tayler R. Fluharty, Katherine K. Thomas, Elizabeth Bukusi, Elly Katabira, Nelly Mugo, Deborah Donnell, Jairam R. Lingappa, Connie Celum, Mark Marzinke, M. Juliana McElrath, Jennifer M. Lund, and Partners PrEP Study TeamLaura PattaciniFred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA, United StatesSearch for more papers by this author, Pamela M. MurnaneUniversity of Washington, Department of Epidemiology, Seattle, WA, United StatesSearch for more papers by this author, Jared M. BaetenUniversity of Washington, Department of Global Health, Seattle, WA, United StatesSearch for more papers by this author, Tayler R. FluhartyFred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA, United StatesSearch for more papers by this author, Katherine K. ThomasUniversity of Washington, Department of Global Health, Seattle, WA, United StatesSearch for more papers by this author, Elizabeth BukusiKenya Medical Research Institute, Centre for Microbiology Research, Nairobi, KenyaSearch for more papers by this author, Elly KatabiraMakerere University, Department of Medicine, Kampala, UgandaSearch for more papers by this author, Nelly MugoKenya Medical Research Institute, Centre for Clinical Research, Nairobi, KenyaSearch for more papers by this author, Deborah DonnellUniversity of Washington, Department of Global Health, Seattle, WA, United StatesSearch for more papers by this author, Jairam R. LingappaUniversity of Washington, Department of Global Health, Seattle, WA, United StatesSearch for more papers by this author, Connie CelumUniversity of Washington, Department of Global Health, Seattle, WA, United StatesSearch for more papers by this author, Mark MarzinkeJohns Hopkins University School of Medicine, Department of Pathology, Baltimore, MD, United StatesSearch for more papers by this author, M. Juliana McElrathFred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA, United StatesSearch for more papers by this author, Jennifer M. LundFred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA, United StatesUniversity of Washington, Department of Global Health, Seattle, WA, United StatesSearch for more papers by this author, and Partners PrEP Study TeamSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5372.abstractAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Pre-exposure Prophylaxis Does Not Enhance HIV-specific T-cell Responses." AIDS Research and Human Retroviruses, 30(S1), p. A176FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Laura Pattacini, Pamela M. Murnane, Jared M. Baeten, Tayler R. Fluharty, Katherine K. Thomas, Elizabeth Bukusi, Elly Katabira, Nelly Mugo, Deborah Donnell, Jairam R. Lingappa, Connie Celum, Mark Marzinke, M. Juliana McElrath, Jennifer M. Lund, and Partners PrEP Study Team.Pre-exposure Prophylaxis Does Not Enhance HIV-specific T-cell Responses.AIDS Research and Human Retroviruses.Oct 2014.A176-A176.http://doi.org/10.1089/aid.2014.5372.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Alternative Effector-Function Profiling Identifies Broad HIV-Specific T-Cell Responses in Highly HIV-Exposed Individuals Who Remain Uninfected

The characterization of host immune responses to human immunodeficiency virus (HIV) in HIV controllers and individuals with high exposure but seronegativity to HIV (HESN) is needed to guide the development of effective preventive and therapeutic vaccine candidates. However, several technical hurdles severely limit the definition of an effective virus-specific T-cell response. By using a toggle-peptide approach, which takes HIV sequence diversity into account, and a novel, boosted cytokine staining/flow cytometry strategy, we here describe new patterns of T-cell responses to HIV that would be missed by standard assays. Importantly, this approach also allows detection of broad and strong virus-specific T-cell responses in HESN individuals that are characterized by a T-helper type 1 cytokine-like effector profile and produce cytokines that have been associated with potential control of HIV infection, including interleukin 10, interleukin 13, and interleukin 22. These results establish a novel approach to improve the current understanding of HIV-specific T-cell immunity and identify cellular immune responses and individual cytokines as potential markers of relative HIV resistance. As such, the findings also help develop similar strategies for more-comprehensive assessments of host immune responses to other human infections and immune-mediated disorders.

Loading dendritic cells with PLA-p24 nanoparticles or MVA expressing HIV genes induces HIV-1-specific T cell responses

Since recent data suggest that nanoparticles and modified vaccinia ankara (MVA) vectors could play a pivotal role in HIV-1 therapeutics and vaccine design, in an ex vivo model of human monocyte-derived dendritic cells (MDDCs), we compared two different loading strategies with HIV-1 vaccine vehicles, either viral or synthetic derived. We used polylactic acid (PLA) colloidal biodegradable particles, coated with HIV Gag antigens (p24), and MVA expressing Gag (rMVA-gag and rMVA-gag/trans membrane) or Tat, Nef and Rev genes (rMVA tat+rev and rMVA nef).PLA-p24 captured by MDDCs from HIV-1 individuals induced a slight degree of MDDC maturation, cytokine and chemokine secretion and migration towards a gradient of CCL19 chemokine and highly increased HIV-specific CD8+ T-cell proliferation compared with p24 alone. After complete maturation induction of PLA-p24-pulsed MDDCs, maximal migration towards a gradient of CCL19 chemokine and induction of HIV-specific T-cell proliferation (two-fold higher for CD4+ than CD8+) and cytokine secretion (IFN-γ and IL-2) in the co-culture were observed.Upon exposure to MVA-gag, MDDCs produced cytokines and chemokines and maintained their capacity to migrate to a gradient of CCL19. MDDCs infected with MVA-gag and MVA-gag trans-membrane were able to induce HIV-specific CD8+ proliferation and secretion of IFN-γ, IL-2, IL-6 and TNF-α.We conclude that both HIV antigens loading strategies (PLA-p24 nanoparticles or MVA expressing HIV genes) induce HIV-1-specific T-cell responses, which are able to kill autologous gag-expressing cells. Thus, they are plausible candidates for the development of anti-HIV vaccines.

CD160 isoforms and regulation of CD4 and CD8 T-cell responses.

BackgroundCoexpression of CD160 and PD-1 on HIV-specific CD8+ T-cells defines a highly exhausted T-cell subset. CD160 binds to Herpes Virus Entry Mediator (HVEM) and blocking this interaction with HVEM antibodies reverses T-cell exhaustion. As HVEM binds both inhibitory and activatory receptors, our aim in the current study was to assess the impact of CD160-specific antibodies on the enhancement of T-cell activation.MethodsExpression of the two CD160 isoforms; glycosylphosphatidylinositol-anchored (CD160-GPI) and the transmembrane isoforms (CD160-TM) was assessed in CD4 and CD8 primary T-cells by quantitative RT-PCR and Flow-cytometry. Binding of these isoforms to HVEM ligand and the differential capacities of CD160 and HVEM specific antibodies to inhibit this binding were further evaluated using a Time-Resolved Fluorescence assay (TRF). The impact of both CD160 and HVEM specific antibodies on enhancing T-cell functionality upon antigenic stimulation was performed in comparative ex vivo studies using primary cells from HIV-infected subjects stimulated with HIV antigens in the presence or absence of blocking antibodies to the key inhibitory receptor PD-1.ResultsWe first show that both CD160 isoforms, CD160-GPI and CD160-TM, were expressed in human primary CD4+ and CD8+ T-cells. The two isoforms were also recognized by the HVEM ligand, although this binding was less pronounced with the CD160-TM isoform. Mechanistic studies revealed that although HVEM specific antibodies blocked its binding to CD160-GPI, surprisingly, these antibodies enhanced HVEM binding to CD160-TM, suggesting that potential antibody-mediated HVEM multimerization and/or induced conformational changes may be required for optimal CD160-TM binding. Triggering of CD160-GPI over-expressed on Jurkat cells with either bead-bound HVEM-Fc or anti-CD160 monoclonal antibodies enhanced cell activation, consistent with a positive co-stimulatory role for CD160-GPI. However, CD160-TM did not respond to this stimulation, likely due to the lack of optimal HVEM binding. Finally, ex vivo assays using PBMCs from HIV viremic subjects showed that the use of CD160-GPI-specific antibodies combined with blockade of PD-1 synergistically enhanced the proliferation of HIV-1 specific CD8+ T-cells upon antigenic stimulation.ConclusionsAntibodies targeting CD160-GPI complement the blockade of PD-1 to enhance HIV-specific T-cell responses and warrant further investigation in the development of novel immunotherapeutic approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0217-y) contains supplementary material, which is available to authorized users.

Group M consensus Gag and Nef peptides are as efficient at detecting clade A1 and D cross-subtype T-cell functions as subtype-specific consensus peptides

ObjectiveEvaluating HIV-1 specific T-cell response in African populations is sometimes compromised by extensive virus diversity and paucity of non-clade B reagents. We evaluated whether consensus group M (ConM) peptides could serve as comparable substitutes for detecting immune responses in clade A and clade D HIV-1 infection. MethodsFrequencies, breadths and polyfunctionality (≥3 functions: IFN-γ, IL-2, TNF-α and Perforin) of HIV-specific responses utilizing ConM, ConA and ConD Gag and Nef peptides was compared. ResultsMedian genetic distances of infecting gag sequences from consensus group M were (8.9%, IQR 8.2–9.7 and 9%, IQR 3.3–10) for consensus A and D, respectively. Of 24 subjects infected with A and D clade virus, Gag responses were detected in comparable proportions of subjects when using ConM peptides 22/24, ConA peptides 17/24, and ConD peptides 21/24; p=0.12. Nef responses were also detected at similar proportions of subjects when using ConM peptides 15/23, ConA peptides 19/23, and ConD peptides 16/23, p=0.39. Virus-specific CD4+ and CD8+ T-cell polyfunctionality were also detected in similar proportions of infected individuals when using different peptide sets. ConclusionsThese data support the use of consensus group M overlapping peptide sets as reagents for detecting HIV-specific responses in a clade A and D infected population, but underscore the limitations of utilizing these reagents when evaluating the breadth of virus-specific responses.

7.0 Managing virological failure

7.0 Managing virological failure

Impact of Autologous Dendritic Cell–Based Immunotherapy (AGS-004) on B- and T-Cell Subset Changes and Immune Activation in HIV-Infected Patients Receiving Antiretroviral Therapy

We previously reported that a combination of antiretroviral therapy with 4 monthly injections of each patient's own autologous dendritic cells (AGS-004) electroporated with CD40 ligand and with HIV RNA antigens obtained from each patient's own pre-antiretroviral therapy plasma induced HIV-specific CD8 T-cell responses in 10 patients. To assess other AGS-004-induced immune changes, we evaluated the modifications in B- and T-cell subsets and the level of immune activation in these patients. The proportion of Bm1 naive cells was increased along with an augmentation of the proliferation marker Ki67. Memory B-cell frequency, CD4 and CD8 T-cell subsets, regulatory T-cell frequency, and CD38/HLA-DR/PD-1 T-cell activation levels remained unchanged after AGS-004 dendritic cell immunotherapy.

Increased Sequence Coverage through Combined Targeting of Variant and Conserved Epitopes Correlates with Control of HIV Replication

A major challenge in the development of an HIV vaccine is that of contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions and induction of HIV-specific T-cell responses recognizing a high number of epitope variants have both been proposed as strategies to overcome this challenge. We addressed the ability of cytotoxic T lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1,300 peptides) using gamma interferon and interleukin-2 (IFN-γ/IL-2) FluoroSpot analysis. While targeting of conserved regions was similar in the two groups (P = 0.47), we found that subjects with control of virus replication demonstrated marginally lower recognition of Gag epitope variants than subjects with normal progression (P = 0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (r = 0.62, P = 0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (r = -0.38, P = 0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (r = 0.50, P = 0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure by which to evaluate the protective potential of future vaccination strategies.

HLA-A*68

Human leukocyte allele (HLA) class I polymorphism has the greatest impact of human genetic variation on viral load set point. A substantial part of this effect is due to the action of HLA-B and HLA-C alleles. With few exceptions the role of HLA-A molecules in immune control of HIV is unclear. We here study HLA-A*68:02, one of the most highly prevalent HLA-A alleles in C-clade infected sub-Saharan African populations, and one that plays a prominent role in the HIV-specific CD8 T-cell responses made against the virus. We define eight epitopes restricted by this allele and propose the peptide binding motif for HLA-A*68:02. Although one of these epitopes almost exactly overlaps an HLA-B*57-restricted epitope in Gag linked with immune control of HIV, this HLA-A*68:02-restricted Gag-TA10 response imposed only weak selection pressure on the virus and was not associated with significantly lower viral setpoint. The only HLA-A*68:02-restricted responses imposing strong selection pressure on HIV were in the flanking regions of Pol-EA8 and Pol-EA11 and within the Vpr-EV10 epitope (P = 8 × 10). However, targeting of this latter epitope was associated with significantly higher viral loads (P = 0.003), suggesting lack of efficacy. This study is consistent with previous data showing that HLA-A-restricted Gag-specific responses can impose selection pressure on HIV. In the case of HLA-A*68:02 the Gag response is subdominant, and apparently has little impact in natural infection. However, these data suggest the potential for high frequency vaccine-induced Gag responses restricted by this allele to have significant antiviral efficacy in vaccine recipients.

HIV‐specific T‐cell responses detected in the genital tract of chronically HIV‐infected women are largely monofunctional

HIV-specific T cells that produce interferon-γ (IFN-γ) are present in the genital tract of HIV-infected women although these do not provide protection against genital HIV shedding. Because polyfunctional HIV-specific T cells have been implicated in better HIV control than those with a single function, this study aimed to investigate whether polyfunctional T cells were present at the female genital mucosa. Cervical cytobrush-derived T cells were obtained from chronically HIV-infected women and compared with blood. CD3(+) T cells from both compartments were expanded with Dynal anti-CD3/CD28 expander beads for 14 days and flow cytometry was used to evaluate four T-cell functions (CD107a, IFN-γ, tumour necrosis factor-α and macrophage inflammatory protein-1β) from 16 women. The majority of Gag-specific T-cell responses in the female genital tract were monofunctional, although low frequencies of HIV Gag-specific polyfunctional CD8(+) T cells were detected at the cervix in 81·3% (13/16) of women. The ability of CD8(+) T cells at both the cervix and in blood to express CD107a and to exhibit polyfunctional responses (two or more functions) following Gag stimulation was inversely associated with plasma viral load and positively associated with blood CD4 counts, suggesting that clinical status impacted on the functionality of HIV-specific T cells at the mucosa, in a similar way to blood. HIV Gag-specific cervical T cells were largely monofunctional. Polyfunctional T cells were detected at the cervix in women with high blood CD4 count and low plasma viral load but these did not protect from HIV genital shedding.

Will it be possible to live without antiretroviral therapy?

Some individuals are able to control HIV infection (either viral replication or chronic immune activation) in the absence of therapy. We will consider recent insights into the mechanisms underlying control in these patients and how this has already encouraged the search for therapeutic approaches to induce a similar HIV functional cure in other patients. Spontaneous reduction of HIV viremia to undetectable levels as observed in a few HIV-infected patients is associated with an efficient HIV-specific CD8 T-cell response, the characteristics of which are now better understood. However, maintenance of such control may involve alternative mechanisms. In particular, the presence of a very small viral reservoir seems necessary, although not sufficient, to ensure HIV control in the long term. Approaches designed to limit the early establishment of these reservoirs, to eliminate infected cells, or to avoid replenishment of the reservoirs have led to HIV remission in the absence of therapy in a few cases. Alternatively, other rare patients seem to deal with HIV infection by controlling immune activation despite high levels of viremia like the natural African monkey hosts do with SIV. These observations suggest that regulation of immune activation should be considered as a serious complement to conventional therapies targeting the virus itself. A better understanding of the mechanisms underlying control of HIV infection or disease in some patients has already led to successful approaches in certain individuals. However, much work is still needed to generalize these results to the global population of HIV-infected patients.

Vaccine and immunotherapeutic interventions

As we enter the fourth decade in HIV epidemic, advances in understanding HIV pathogenesis and development of potent and safer antiretroviral drugs have been spectacular. More than 30 antiviral drugs have been registered and the impact of combination antiviral therapy on morbidity and mortality has been dramatic. However, despite long-term virus suppression, HIV invariably rebounds after interruption of therapy. Long-term antiviral therapy does not cure HIV infection nor does it induce restoration/development of virus-specific immune responses capable of controlling HIV replication. Therefore, development of immune-based interventions is needed to restore effective defenses that can lead to HIV functional cure and ultimately eradication. Therapeutic vaccination and immune interventions that generate de-novo or that boost preexisting HIV-specific T-cell responses are being investigated as a potential means to achieve a 'functional HIV cure'. One major hurdle in the quest of an HIV cure is control and elimination of the HIV latent reservoir. Several immune interventions that target the latent reservoir have been tried in recent years. In parallel, several therapeutic vaccination strategies have been developed and tested in early clinical studies. Recent encouraging studies show for the first time that vaccination can have an impact on HIV load. This review summarizes the main immune interventions evaluated over the last years. Ways to improve them, as well as challenges in monitoring/evaluating effects of such strategies, are being discussed. In addition, clinical efficacy and potential clinical benefits of immunotherapeutic interventions are particularly difficult to measure. This review highlights current assays used and their shortcoming.

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 + T-Cell Antiviral Activity and Correlates with Preservation of the CD4 + T-Cell Compartment

The important role of the CD8(+) T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8(+) T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8(+) T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4(+) T-cell set points were observed in PHI subjects with higher HIV-specific CD8(+) T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-γ. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1β (MIP-1β). All together, this study underscores the importance of CD8(+) T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection.

Therapeutic Vaccination Expands and Improves the Function of the HIV-Specific Memory T-Cell Repertoire

The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy. In this double-blind study, 17 HIV-infected individuals with viral loads of <50 copies/mL and CD4(+) T-cell counts of >350 cells/µL were randomly assigned to the vaccine or placebo arm. Vaccine recipients received 3 intramuscular injections of HIV DNA (4 mg) coding for clade B Gag, Pol, and Nef and clade A, B, and C Env, followed by a replication-deficient adenovirus type 5 boost (10(10) particle units) encoding all DNA vaccine antigens except Nef. Humoral, total T-cell, and CD8(+) cytotoxic T-lymphocyte (CTL) responses were studied before and after vaccination. Single-copy viral loads and frequencies of latently infected CD4(+) T cells were determined. Vaccination was safe and well tolerated. Significantly stronger HIV-specific T-cell responses against Gag, Pol, and Env, with increased polyfunctionality and a broadened epitope-specific CTL repertoire, were observed after vaccination. No changes in single-copy viral load or the frequency of latent infection were observed. Vaccination of individuals with existing HIV-specific immunity improved the magnitude, breadth, and polyfunctionality of HIV-specific memory T-cell responses but did not impact markers of viral control. NCT00270465.

Research brief

Combination antiretroviral therapy (cART) improves the survival of HIV-infected patients but lifelong treatment is needed to prevent viral rebound. Now, a small randomised placebo-controlled trial suggests that therapeutic immunisation with a dendritic-cell-based vaccine may offer an alternative to lifelong cART. Patients on cART were immunised with autologous monocyte-derived dendritic cells that had been pulsed with autologous heat-inactivated HIV or treated with control dendritic cells. In the immunised individuals, the plasma viral load setpoint was decreased at 12 weeks and 24 weeks after cART interruption and HIV-specific T-cell responses had increased.

Safety and Immunogenicity of DNA Prime and Modified Vaccinia Ankara Virus-HIV Subtype C Vaccine Boost in Healthy Adults

A randomized, double-blind, placebo-controlled phase I trial was conducted in 32 HIV-uninfected healthy volunteers to assess the safety and immunogenicity of 3 doses of DNA vaccine (Advax) plus 1 dose of recombinant modified vaccinia virus Ankara (MVA) (TBC-M4) or 3 doses of TBC-M4 alone (groups A and B, respectively). Both vaccine regimens were found to be safe and well tolerated. Gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assay responses were detected in 1/10 (10%) individuals in group A after three Advax primes and in 9/9 individuals (100%) after the MVA boost. In group B, IFN-γ ELISPOT responses were detected in 6/12 (50%) and 7/11 (64%) individuals after the second and third MVA vaccinations, respectively. Responses to all vaccine components, but predominantly to Env, were seen. The breadth and magnitude of the T cell response and viral inhibition were greater in group A than in group B, indicating that the quality of the T-cell response was enhanced by the DNA prime. Intracellular cytokine staining indicated that the T-cell responses were polyfunctional but were skewed toward Env with a CD4(+) phenotype. At 2 weeks after the last vaccination, HIV-specific antibody responses were detected in all (100%) group B and 1/11 (9.1%) group A vaccinees. Vaccinia virus-specific responses were detected in all (100%) group B and 2/11 (18.2%) group A vaccinees. In conclusion, HIV-specific T-cell responses were seen in the majority of volunteers in groups A and B but with a trend toward greater quality of the T-cell response in group A. Antibody responses were better in group B than in group A.