After over 30 years of intense research, an effective HIV type 1 (HIV-1) vaccine remains elusive. Vaccines for non-integrating viruses such as influenza, smallpox, and measles elicit robust B cell neutralizing antibody and T cell responses that provide protection from clinical disease (). For HIV-1, passive transfer of potent broadly neutralizing antibodies (bnAbs) to rhesus macaques confers sterilizing protection to chimeric simian/human-immunodeficiency virus (SHIV) challenge (). Similarly, adenovirus-vectored immunogens confer partial protection from simian immunodeficiency virus (SIV) infection (), while attenuated rhesus cytomegalovirus (RhCMV)-vectored immunogens induce CD8T cell responses that clear SIV infection in over half of vaccinated animals (). Despite these early promising findings, only one of five HIV-1 vaccine efficacy trials in humans, the RV144 vaccine trial in Thailand testing the canarypox prime, gp120, ALVAC/gp120 B/E vaccine, has shown any protection from transmission, with an estimated vaccine efficacy of 31.2% (). Although the mechanism of protection remains incompletely understood, an RV144 immune correlates analysis raised the hypothesis that reduced transmission risk in this trial was mediated by antibody binding to the HIV envelope glycoprotein (Env) and initiation of antibody-dependent cellular cytotoxicity (ADCC) (). The marginal success of these preclinical and clinical vaccine trials highlights the complexity of host immune responses to HIV-1 and the challenges associated with developing a vaccine that can elicit protective B or T cell responses. This review highlights some of these challenges and potential avenues to overcome them.

Although innate immune activation can promote viral replication, there is increasing evidence that innate responses activated early on mediate potent antiviral activity that contributes to the HIV-1 transmission bottleneck. Studies in macaques have shown that plasmacytoid dendritic cells recruited to the site of virus entry () secrete cytokines and chemokines, including type I interferons (IFNs). This induces a rapid innate immune response through the upregulation of IFN-stimulated genes (ISGs), many of which have potent anti-HIV-1 activity (). Furthermore, treatment of rhesus macaques with IFNα2 increased the number of intrarectal challenges required for systemic SIVmac infection and decreased the number of TF viruses (), indicating that increased levels of type 1 IFNs in the mucosa at the initial sites of viral replication has a substantial protective effect. Consistent with this, HIV-1 TF viruses are commonly less sensitive to inhibition by type 1 IFNs than viruses that predominate during chronic infection (), but IFN resistance decreases rapidly over time in part as a result of immune escape mutations (). These results suggest that type 1 IFNs exert considerable selective pressure on the transmitted virus pool, ( Figure 1 ). A careful dissection of the innate immune mechanisms that both combat and aid HIV-1 replication at the site of entry may help guide rational vaccine design.

Envs from TF viruses also frequently contain shorter variable loops (V1–V5) and fewer glycosylation sites that can prevent antibody recognition, than Envs from chronically infected individuals. Thus, the question arose whether TF viruses might be more neutralization sensitive (). One early study of heterosexual transmission reported that Envs from acutely infected recipients were uniquely sensitive to neutralization by plasma from their respective donors, although this was not observed for plasma from other infected individuals (). However, subsequent studies of large numbers of TF Envs showed that they were invariantly resistant to heterologous neutralization (). Dissection of the antibody response in chronically infected individuals provided a plausible explanation (): common CD4 binding site (CD4bs) and third variable (V3) loop directed monoclonal antibodies, which were unable to neutralize heterologous tier 2 (difficult-to-neutralize) viruses, were nonetheless capable of neutralizing autologous tier 2 viruses and selected for viral escape mutations (). These results indicated that the autologous neutralization potently constrains the native Env trimer to a conformationally closed state, thus explaining the neutralization-resistant phenotype of TF viruses.

CAPRISA Acute Infection Study and the Center for HIV-AIDS Vaccine Immunology Consortium Comparison of viral Env proteins from acute and chronic infections with subtype C human immunodeficiency virus type 1 identifies differences in glycosylation and CCR5 utilization and suggests a new strategy for immunogen design.

CAPRISA Acute Infection Study and the Center for HIV-AIDS Vaccine Immunology Consortium Comparison of viral Env proteins from acute and chronic infections with subtype C human immunodeficiency virus type 1 identifies differences in glycosylation and CCR5 utilization and suggests a new strategy for immunogen design.

Studies in experimentally infected macaques and human mucosal explant cultures have shown that HIV-1 is first intercepted by intraepithelial Langerhans or mucosal dendritic cells, which pass the transmitted viruses on to resident CD4T cells without themselves becoming productively infected (). In the macaque model, the resident CD4T cells exhibit a “resting” phenotype, characterized by the lack of classical activation markers and low-level expression of the HIV-1 co-receptor CCR5. Macrophages, which are also present, do not play a significant role. Consistent with these findings, TF viruses almost exclusively use CD4 and CCR5, respectively, as their receptor and co-receptor and replicate efficiently in activated CD4T cells but not macrophages. Moreover, analysis of a large panel of full-length infectious molecular clones demonstrated that TF viruses are twice as infectious and contain twice as much Env compared to viruses that predominate during chronic infection (). TF viruses are also captured twice as efficiently by monocyte-derived dendritic cells and are more readily transferred to CD4T cells than chronic viruses. Thus, higher Env content, increased cell-free infectivity and improved dendritic cell interaction likely contribute to the ability of the TF virus to gain a foothold in the new host ( Figure 1 ).

Many factors influence whether virus exposure at mucosal surfaces leads to productive infection, including the virus load in the infecting partner, the integrity of the mucosa, target cell availability in mucosal and submucosal tissues, immune activation, genital inflammation, and altered mucosal microbiota (). In addition, there is increasing evidence that the transmission process selects for viruses with enhanced transmission fitness ( Figure 1 ). By comparing protein sequences of the major viral structural proteins Gag and Pol as well as the accessory protein Nef from 137 heterosexual transmission pairs, Carlson and colleagues found that viruses with amino acid residues matching the consensus sequence of the study population were preferentially transmitted (). This finding is consistent with previous observations that most within-host diversification reduces transmission fitness and represents an evolutionary dead-end at a population level (). The observed selection was more stringent in female-to-male than male-to-female transmissions and was mitigated by factors that elevate transmission risk such as higher donor viral loads, genital ulcer disease, and genital tract inflammation ().

Mucosal transmission reduces the genetic and phenotypic diversity of the donor HIV-1 quasi-species to only one or very few variants that seed infection in the recipient. Viruses that traverse the mucosa, but are defective or fail to initiate a productive infection (i.e., have a basic reproductive ratio Rof lower than 1), will be extinguished. In contrast, the mucosal bottleneck selects for viruses with a high transmission fitness. Although the biological properties that comprise this phenotype remain to be fully elucidated, a high replicative capacity, increased infectivity, enhanced dendritic cell interaction, and greater resistance to the antiviral effects of type 1 interferons (IFNs) are likely to contribute ().

Understanding the viral and host factors that contribute to the mucosal bottleneck may inform vaccine design. One approach to dissect transmission barriers is to study the genotype and phenotype of viruses that establish new infections. Humans cannot be sampled at the moment of transmission, but by analyzing plasma viral sequences from acutely infected individuals, it is possible to infer the genomes of the viruses that had initiated productive infection weeks earlier (). In the absence of adaptive immune responses, HIV-1 diversifies in an essentially random fashion. As a consequence, viral sequences that evolve from individual transmitted founder (TF) viruses exhibit a Poisson distribution of mutations and a star-like phylogeny that coalesces to an inferred consensus sequence at or near the time of transmission (). Using single template amplification, which generates HIV-1 sequences devoid of PCR artifacts, it was shown that in ∼80% of heterosexual transmission cases, a single virus was responsible for establishing the new infection (). The same approach revealed that ∼40% of men who have sex with men (MSM) and ∼60% of intravenous drug users (IVDUs) acquired two or more variants that led to productive infection. The higher multiplicity of HIV-1 infection observed in MSM and IVDU is consistent with a higher epidemiological risk of virus acquisition and suggests a greater challenge for HIV-1 vaccines.

The majority (∼70%) of HIV-1 infections worldwide result from heterosexual contact, which in the absence of confounding risk factors (e.g., genital ulceration), is generally an inefficient process. This is reflected in a mucosal bottleneck that reduces the genetic diversity of the HIV-1 quasispecies in the transmitting donor to only one or very few variants that seed the recipient (). This virus population bottleneck is likely due to both stochastic and selective forces in the mucosal tissues that act during the transmission process where virus is most vulnerable to elimination.

The study of antibody-virus co-evolution in the CH505 individual revealed that two distinct B cell lineages can act “cooperatively” in driving bnAb development: one cooperating B cell lineage selected for TF virus escape mutants that were resistant to that lineage but that enhanced sensitivity to neutralization by a second bnAb lineage ( Figure 4 ) (). In a case of V3 glycan bnAb B cell lineage induction, plasma autologous neutralizing antibodies selected an escape mutant creating a new V3-glycan epitope essential for bnAb Env recognition (). Similarly, Bonsignori et al. (Keystone Symposia 2015) have found multiple cooperating B cell lineages for V3-glycan bnAbs. In addition to the importance of cooperating lineages for understanding how bnAbs develop, the elucidation of such lineages allows emergence of patterns of Env sensitivity and resistance to these lineages to be defined through time, enabling the definition of key mutations that impact the evolution of antibody breadth; such information can be directly employed to inform vaccine antigen design.

The TF virus induces both a broadly neutralizing antibody (bnAb) lineage (CH103 lineage in red) as well as a second lineage (the CH235 cooperating lineage in blue). The TF directly drives the bnAb lineage while the cooperating antibody lineage selects virus escape mutants that bind to and are neutralized by the bnAb lineage. Thus, in this case, the bnAb lineage is initiated by the TF virus and is driven by escape mutants from other cooperating lineages.

The first individual studied from the time of transmission to bnAb development (known as CH505) produced bnAbs that predominantly recognized the CD4bs via the heavy chain third complementarity determining region (HCDR3) and had one TF virus that initiated the infection (). Binding of the TF Env to the bnAb unmutated common ancestor (UCA) B cell antigen receptor (BCR) induced the bnAb lineage, followed by intense selection of virus escape-mutations and envelope (Env) epitope diversification, that preceded acquisition of plasma bnAb activity. These observations are consistent with the hypothesis that exposure to autologous variants that confer some degree of resistance to antibodies may foster selection of antibodies during affinity maturation with extended capacity to recognize virus variants ().recently made similar observations about the development of V1V2-glycan bnAb targeted bnAbs.

Single genome sequencing has been used to fine-map the evolution of TF viruses in prospectively followed individuals by sequencing their plasma virus over the course of infection. Within a few months of infection (), TF viruses are almost completely replaced by viruses differing at several highly selected genomic loci, initially predominantly mediated by immune escape from cytotoxic T cells (CTLs) (). Extending this approach into longitudinal studies spanning years, we and others have mapped HIV-1 diversification in several individuals who developed broad and potent neutralizing antibodies, revealing that a virus-antibody “arms race” ensues in which the HIV-1 TF Env induces autologous neutralizing antibodies that can neutralize the TF virus and drive selection of virus escape mutants ( Figure 2 ) (). This process is repeated throughout virus evolution, leading to the induction of neutralizing antibodies with varying degrees of cross-reactive breadth, such that sera from 50% of HIV-1-infected individuals can neutralize ∼50% of primary viruses, and ∼15%–20% of HIV-1 infected individuals have potent bnAbs with extensive breadth (). While some degree of breadth in bnAb development is common, bnAbs with a high degree of potency and breadth require prolonged development, taking ∼2–4 years (). Study of HIV-1-infected individuals have provided a rich source for isolation of a large number of bnAbs (), many of which are now being developed for passive administration to prevent and treat HIV-1 infection (). These bnAbs predominantly recognize Env that mediates entry into target cells by binding to CD4 and CCR5 or CXCR4 and consists of a trimer of gp120 and gp41 heterodimers. Identification of recurrent antibody targets suggest there are five main targets for bnAbs on the HIV-1 Env trimer: the CD4 binding site (bs), the V3- and V1V2-glycan sites, gp120-gp41 bridging bnAbs, and the gp41 membrane proximal external region (MPER) ( Figure 3 ) (). Phase I clinical trials have been completed with CD4 binding site bnAbs 3BNC117 () and VRC01 () with the goal of developing them for both preventative and therapeutic uses.

Co-crystal structure of the HIV-1 trimer () with gp120 in blue and gp41 in gray. The five areas targeted by broadly neutralizing antibodies are the CD4 binding site (orange), V1V2 glycans (red), V3 glycans (green), gp120-gp41 bridging site (purple), and the MPER (dark red). The area of insertion of the envelope trimer into the membrane is noted by the transmembrane domain and the gp160 cytoplasmic domain is noted.

The initial transmission event of sexually transmitted HIV-1 is mediated by one transmitted founder (TF) virus. The TF virus induces an initial antibody response, called the autologous neutralizing antibody, that is specific for the TF virus. The autologous neutralizing antibody neutralizes the TF but rapidly selects virus escape mutants, which in turn induces new antibody specificities. This process is repeated throughout virus evolution such that after years of infection, a spectrum of cross-reactive neutralizing antibodies are induced, with ∼20% of chronically infected individuals making high levels of very broadly reactive neutralizing antibodies.

CHAVI Clinical Core B The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection.

The higher frequencies of autoreactivity and/or polyreactivity among HIV-1 bnAbs () suggest that conserved, neutralizing epitopes present on the HIV-1 Env may have been selected to resemble host determinants (). Studies of knockin mice that express the V(D)J rearrangements of human bnAbs or their germline ancestors (), and the identification of host antigens that structurally resemble or are identical to HIV-1 determinants, both support this hypothesis (). Thus, a key hypothesis pursued by our group is that HIV-1 infection induces immune perturbations that relax immune tolerance controls and eventually promote the expression of bnAbs with traits of antibodies normally disfavored by immune tolerance mechanisms ().

Common tolerance mechanisms, but distinct cross-reactivities associated with gp41 and lipids, limit production of HIV-1 broad neutralizing antibodies 2F5 and 4E10.

All bnAbs have one or more unusual antibody traits: long hydrophobic HCDR3s, autoreactivity, and high frequencies of somatic mutations, all traits associated with triggering of B cell deletion or anergy by immune tolerance (). Thus, immune tolerance controls may constrain vaccinees’ ability to make bnAbs (). Moreover, HIV-1 Env is highly glycosylated and glycans shield critical neutralizing antibody target sites (). Env carbohydrates are synthesized by the host glycosylation machinery and have been proposed to be poorly immunogenic by mimicking self glycans (). Despite this, carbohydrates are often critical components of bnAb epitopes, for example, the V1V2 and V3 glycan bnAbs.

BnAb vaccines may further require limiting host tolerance controls on disfavored bnAb lineages, a strategy we term Vaccine Transient Immune Modulation (VTIM). VTIM is modeled after cancer immunotherapy immune checkpoint blockades (), based on the recognition that tumors may commandeer peripheral tolerance to persist. The most successful of these interfere with the engagement of T cell checkpoint receptors and their ligands (). A similar conceptual approach could be employed to enable expansion of the primary B cell repertoire to include specificities normally limited by central tolerance.

CD4 T follicular helper cells (T) were first recognized by their association with normal and cancerous germinal centers (GCs) () and subsequently shown to be antigen-specific CD4immigrants into the B cell follicle necessary for both GC B cell survival and for the somatic evolution of B cell populations toward higher affinity (). Immune checkpoints also control the function of Tand prevent systemic autoimmune disease mediated by autoantibodies (). Tenforce peripheral tolerance on GC B cells via mechanisms that are not yet elucidated (). Tare more frequent in the blood of HIV-infected individuals with comparatively high plasma bnAb activity (). Immunization regimens that selectively induce increased Tfor Env antibody induction are under development.

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance.

The unique features of bnAbs, both the extensive somatic hypermutation and the host tolerance controls that constrain their development, suggest a need for an appropriate immunologic environment for their induction. This includes adequate CD4 + T cell help and relaxation of host tolerance mechanisms at the time of vaccination.

From the antibody-virus evolution work discussed above, sequential gp120 Env monomer immunogens have been designed to study the ability of sequential TF mutant Env immunizations to recreate the Env events that drive bnAb development (). Similarly, Moore et al. have identified the mutations that were key for V1V2 bnAb development in an HIV-1-infected African individual and have proposed a sequential Env immunization regimen for inducing V1V2 bnAbs ().

In early studies of bnAbs, it was noted that only a few of the bnAb UCAs reacted with heterologous HIV-1 envelope proteins. However, studies of HIV-1-infected individuals from the time of transmission until development of bnAbs have shown that many TF Envs bind antigen receptors of bnAb UCAs and are therefore key to driving bnAb development. The HIV-bnAb co-evolution studies suggested selecting sequential Env immunogens that target germline UCA antibodies and the receptors of subsequent lineage intermediates (). Using immunogens optimized for binding to specific BCRs (e.g., UCA, subsequent intermediates, and finally bnAb precursors), we propose to provide a selective growth and development advantage to the B cell lineages with the greatest potentials for producing bnAbs with high potency and breadth (). BnAb B cell lineages of CD4bs bnAbs () and V1V2-glycan antibodies () are similar in VH usage, bnAb structures, and recognition of specific Envs by bnAb germline antibodies, regardless of the individuals from whom they were isolated. Thus, immunogens designed from one individual may successfully drive bnAb lineages in others.

Recently, several structures of HIV-1 Env trimers have been reported, with the highest resolution obtained using a soluble Env trimer containing stabilizing mutations that enhance interactions between the gp41 subunits, designated BG505 SOSIP () ( Figure 3 ). The main rationales for use of an Env trimer immunogen are (1) native trimers do not express non-neutralizing epitopes to divert protective immune responses, (2) they display bnAb epitopes in correct orientations to facilitate the activation of bnAb UCAs, and (3) multiple epitopes will be present, potentially giving rise to polyclonal antibody responses that target different epitopes, thus limiting the potential for resistant variants to evade a vaccine response. Currently, the best-defined “native-like” Env vaccine is the soluble BG505 SOSIP; however, this immunogen only elicited antibodies that mediate neutralization of the autologous BG505 Env, with no heterologous HIV-1 neutralization reported (). Recently, membrane-bound trimers on virus-like particles (VLPs) have been produced and were found to induce occasional tier 2 neutralizing antibodies for viruses with deleted glycans ().

Jardine and colleagues have designed a series of immunogens that mimic the CD4bs and bind well to the UCA of the CD4bs bnAb, VRC01, and activate the VRC01 UCA B cell receptor in the context of VRC01 UCA variable heavy (VH) knockin mice (). Similarly,have driven a VRC01 antibody lacking key mutations to further mature and make plasma bnAb activity in a bnAb VH knockin mouse system. Prototype gp41 bnAbs are 2F5, which binds at the MPER N terminus, and 4E10 and 10E8, which bind at the C terminus (). 2F5, 4E10, and 10E8 are autoreactive (), and in knockin mice that express the 2F5 or 4E10 BCR, B cell development is blocked by clonal deletion in the bone marrow (). All three have a long hydrophobic HCDR3 that interacts with lipid membranes ()—a trait necessary for binding to and neutralization of HIV-1 (). Because of the involvement of the virion membrane in the epitopes, minimal MPER peptide-liposome immunogens have been designed that project the MPER bnAb epitopes in a manner similar to that seen in the virion (). In knockin mice containing VH and variable light (VL) chains for 2F5 bnAb, an MPER peptide-liposome induced the few anergic peripheral B cells that escaped deletion to produce high levels of plasma bnAbs (). Immunizing unmutated ancestor (UA) 2F5 VH and VL mice with an MPER peptide-liposome has initiated the UA 2F5 lineage (L. Verkoczy and B.F. Haynes, personal communication).

Common tolerance mechanisms, but distinct cross-reactivities associated with gp41 and lipids, limit production of HIV-1 broad neutralizing antibodies 2F5 and 4E10.

Minimal Env immunogens range from small glycopeptides to monomer Env subunits and have the potential to focus the immune response on a vulnerable epitope. For the V1V2- and V3-glycan bnAb epitopes, synthetic glycopeptides have been produced (). The best-studied minimal immunogens have been developed for the CD4bs () and for the MPER ().

The pre-existing CD4 T cell repertoire in HIV-1 uninfected individuals also contains T cells that cross-react with both HIV-1 and microbiome peptides (). This implies that previous exposure to immunogens from many sources may influence the primary immune response to an agent such as HIV-1, probably influencing the immunodominance of the responding T cells. Thus, both the CD4 T cell repertoire and the B cell repertoire are primed to respond to HIV-1 antigens due to the presence of microbiome-HIV cross-reactive antigens. These findings have provided a rationale for either deleting or modifying cross-reactive Env epitopes to minimize non-neutralizing dominant antibody responses induced by HIV-1 immunogens.

The first antibodies to arise after HIV-1 transmission are to Env gp41, at ∼13 days post-transmission (). The predominant specificity of plasma cells in acute HIV-1 infection (AHI) in both blood and terminal ileum is directed to gp41 (). Many of these gp41 antibodies were class-switched to IgG, mutated, and polyreactive to host and environmental antigens, including the microbiome. Thus, we hypothesized that the microbiome primed and expanded the pre-infection B cell repertoire to be cross-reactive with gp41, enabling stimulation by HIV-1 gp41 at the time of AHI (). Recently, a DNA prime, recombinant adenovirus (rAd5) boost vaccine containing both env gp120 and gp41 was tested in an efficacy trial (). Vaccinees had a dominant gp41 antibody response both in serum and in the memory B cell repertoire. These gp41 antibodies were non-neutralizing and polyreactive for host and microbiome antigens. A study of the pre-vaccination B cell repertoire proved the presence of a pre-existing pool of microbiome-gp41 cross-reactive B cells that was stimulated by the vaccine ().

Initial B-cell responses to transmitted human immunodeficiency virus type 1: virion-binding immunoglobulin M (IgM) and IgG antibodies followed by plasma anti-gp41 antibodies with ineffective control of initial viremia.

The points discussed above are also relevant to the design of T-cell-based HIV therapeutic strategies. Here, induction of a breadth of co-dominant responses is important not only to prevent de novo escape but also to enable targeting of responses to additional epitopes that latent virus has not already escaped (). Targeting of epitopes that are rapidly and continuously displayed on cells following reactivation of latent virus is also a priority. In addition, therapeutic strategies need to overcome the defects in immune function, including the decline in CD8T cell antiviral activity induced by prior high-level virus replication.

Associations between HLA alleles and/or responses of particular protein/epitope specificity and HIV-1 control also give insight into the relative antiviral efficacy of different CD8T cell responses. The association of responses to Gag epitopes and HLA alleles that restrict immunodominant Gag responses is attributable in part to the rapid presentation of Gag derived from infecting virions on HIV-infected cells, which enables them to be targeted by CD8T cells prior to MHC class I downregulation ().

T cell escape mutations are selected if the replicative advantage conferred by the mutation is outweighed by any costs of the mutation to intrinsic viral fitness. The most rapidly escaped responses are selected by immunodominant T cells targeting epitopes in variable viral sequences where mutations are readily accommodated (). Hence, broadly directed, co-dominant responses to conserved epitopes where escape incurs high fitness costs, in the absence of compensatory mutations, are associated with good HIV-1 control (). The associations between CD8T cell responses to particular viral proteins and/or epitopes and the efficiency of HIV-1 control () are due in part to their relative sequence conservation. Likewise, associations between certain HLA class I alleles and better virus control are partly attributable to epitope conservation and the fitness costs of mutational escape (). Thus, it should be beneficial for T-cell-inducing HIV-1 vaccines to focus on conserved viral epitopes.

Relationship between functional profile of HIV-1 specific CD8 T cells and epitope variability with the selection of escape mutants in acute HIV-1 infection.

HIV-1 evades CD8 + T-cell-mediated control during acute infection by rapid evolution of escape mutations in and around the epitopes targeted by CD8 + T cells and by downregulation of MHC class I levels on the surface of infected cells to reduce CD8 + T cell recognition. HIV-1 elimination is further hampered by infection of CD4 + cells in sites such as lymph node GCs, which are poorly accessed by CD8 + T cells, and by the rapid establishment of a reservoir of latently infected cells. Continued high-level antigenic stimulation by persisting virus, exacerbated by defects in CD4 + T cell function, leads to exhaustion of CD8 + T cell antiviral activity that further impairs control of viral replication from early infection onward.

To complement antibody-mediated protection, there is also a need for vaccines to induce cellular immune responses capable of eradicating or effectively containing virus replication following the establishment of HIV-1 infection. Although strong virus-specific CD8T cell responses are activated during acute HIV-1 infection, they fail to eliminate the virus (). Analysis of HIV’s strategies for evasion of T cell control and features of virus-specific CD8T cell responses that are associated with superior virus control helps inform the rational design of T-cell-based vaccine strategies.

CHAVI Clinical Core B The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection.

T Cell Responses Elicited by Select Vaccine Vectors

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Ottenhoff T.H. Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity. Lewinsohn et al., 1998 Lewinsohn D.M.

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Grabstein K.H. Characterization of human CD8+ T cells reactive with Mycobacterium tuberculosis-infected antigen-presenting cells. It is likely, though not yet certain, that the atypical CD8 T cell responses are essential for the protection. These T cell responses are dependent on the RhCMV gene US11, which downregulates classical MHC1a expression, and on the absence of the UL128/130 genes, which determine virus tropism for epithelial and endothelial cells (). The CMV must also impair the cross-priming process that is normally important for generation of classical T cell responses. There is a similarity to primary T cell responses to mycobacterial antigens in humans, which are primarily class II restricted CD4 T cells and HLA-E restricted CD8 T cells ().

Irvine et al., 2002 Irvine D.J.

Purbhoo M.A.

Krogsgaard M.

Davis M.M. Direct observation of ligand recognition by T cells. It is clear that, at least in the protected monkeys, SIV-infected cells must express some of the same peptides in MHC-E and MHC-II so that they are recognized by the vaccine-stimulated T cells. They may be expressed in low numbers, because CD8 T cells can recognize cells expressing <20 epitope peptides per cell (). The level is probably insufficient to prime T cell responses.

Joosten et al., 2010 Joosten S.A.

van Meijgaarden K.E.

van Weeren P.C.

Kazi F.

Geluk A.

Savage N.D.

Drijfhout J.W.

Flower D.R.

Hanekom W.A.

Klein M.R.

Ottenhoff T.H. Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity. HLA-E-restricted HIV-reactive CD8 T cells have not yet been shown, but humans do make broad CD8 T cell responses to mycobacterial antigens (). It is likely that similar HIV-specific T cells could be stimulated by a vaccine. Similarly HLA-II-restricted CD8 T cells are normally rare. For both to be considered as targets for vaccine design it will be necessary to show that HIV-infected cells express these antigens on their surface.

If direct translation of a CMV-vectored vaccine to humans is not yet practical, responses that are much broader than generated by current human vaccine candidates ( Figure 5 ) might still be effective, especially if there was good match of vaccine to virus. There are two promising approaches to this problem, focusing on conserved regions, and using mosaic strategies to design antigens.