Potential Correlates Of Protection Research Articles

Circulating Mycobacterium tuberculosis DosR latency antigen-specific, polyfunctional, regulatory IL10+ Th17 CD4 T-cells differentiate latent from active tuberculosis

The functional heterogeneity of T cell responses to diverse antigens expressed at different stages of Mycobacterium tuberculosis (Mtb) infection, in particular early secreted versus dormancy related latency antigens expressed later, that distinguish subjects with latent (LTBI), pulmonary (PTB) or extrapulmonary (EPTB) tuberculosis remains unclear. Here we show blood central memory CD4 T-cell responses specific to Mtb dormancy related (DosR) latency, but not classical immunodominant secretory antigens, to clearly differentiate LTBI from EPTB and PTB. The polyfunctionality score integrating up to 31 DosR-specific CD4 T-cell functional profiles was significantly higher in LTBI than EPTB or PTB subjects. Further analysis of 256 DosR-specific T-cell functional profiles identified regulatory IL10 + Th17 cells (IL10+IL17A+IL17F+IL22+) to be significantly enriched in LTBI; in contrast to pro-inflammatory Th17 cells (IFNγ+IL17A+/IL10−) in the blood and lung of EPTB and PTB subjects respectively. A blood polyfunctional, Mtb DosR latency antigen specific, regulatory, central memory response is therefore a novel functional component of T-cell immunity in latent TB and potential correlate of protection.

Antibody Epitopes Identified in Critical Regions of Dengue Virus Nonstructural 1 Protein in Mouse Vaccination and Natural Human Infections

Dengue is a global public health problem and is caused by four dengue virus (DENV) serotypes (DENV1-4). A major challenge in dengue vaccine development is that cross-reactive anti-DENV Abs can be protective or potentially increase disease via Ab-dependent enhancement. DENV nonstructural protein 1 (NS1) has long been considered a vaccine candidate as it avoids Ab-dependent enhancement. In this study, we evaluated survival to challenge in a lethal DENV vascular leak model in mice immunized with NS1 combined with aluminum and magnesium hydroxide, monophosphoryl lipid A + AddaVax, or Sigma adjuvant system+CpG DNA, compared with mice infected with a sublethal dose of DENV2 and mice immunized with OVA (negative control). We characterized Ab responses to DENV1, 2, and 3 NS1 using an Ag microarray tiled with 20-mer peptides overlapping by 15 aa and identified five regions of DENV NS1 with significant levels of Ab reactivity in the NS1 + monophosphoryl lipid A + AddaVax group. Additionally, we profiled the Ab responses to NS1 of humans naturally infected with DENV2 or DENV3 in serum samples from Nicaragua collected at acute, convalescent, and 12-mo timepoints. One region in the wing domain of NS1 was immunodominant in both mouse vaccination and human infection studies, and two regions were identified only in NS1-immunized mice; thus, vaccination can generate Abs to regions that are not targeted in natural infection and could provide additional protection against lethal DENV infection. Overall, we identified a small number of immunodominant regions, which were in functionally important locations on the DENV NS1 protein and are potential correlates of protection.

Antibody epitopes identified in critical regions of dengue virus nonstructural 1 protein in mouse vaccination and natural human infections

Abstract A major challenge in dengue vaccine development is that cross-reactive anti-DENV antibodies (Abs) can be protective or potentially enhance disease via antibody-dependent enhancement (ADE). We recently showed that immunization with adjuvanted recombinant NS1 from all four DENV serotypes protects against DENV2 challenge in a mouse model of lethal vascular leak syndrome. Conversely, we found that DENV NS1 by itself triggers endothelial permeability in vitro and vascular leak in vivo. Here, we evaluated survival to lethal DENV challenge in mice immunized with (1) NS1+alum; (2) NS1+Monophosphoryl Lipid A and AddaVax (MA); (3) NS1+Sigma adjuvant system and CpG DNA (SCpG); (4) ovalbumin+adjuvant (OVA); or (5) a sublethal dose of DENV2 strain PLO46.NS1. OVA or NS1+alum immunized mice were not protected, whereas immunization with NS1+MA or NS1+SCpG or DENV2-PL046 resulted in 100% survival. We characterized Ab responses to NS1 from DENV1-3 using an antigen microarray tiled with 20-mer peptides overlapping by 15 amino acids and identified 5 regions with significant levels of antibody reactivity in the NS1+MA group. We also profiled Ab responses to NS1 in humans naturally infected with DENV-2 or -3 in longitudinal serum samples from Nicaragua. One region in the NS1 “wing” domain was immunodominant in both mouse and human studies, and two regions were identified only in NS1-immunized mice; thus, vaccination can generate Abs to regions that are not targeted in natural infection and could provide additional protection against a lethal DENV infection. Overall, we identified several immunodominant regions, which were in functionally important locations on the DENV NS1 protein and are potential correlates of protection.

B-Cell Responses to Intramuscular Administration of a Bivalent Virus-Like Particle Human Norovirus Vaccine

ABSTRACTHuman noroviruses (HuNoVs) are a leading cause of acute gastroenteritis worldwide. A virus-like particle (VLP) candidate vaccine induces the production of serum histo-blood group antigen (HBGA)-blocking antibodies, the first identified correlate of protection from HuNoV gastroenteritis. Recently, virus-specific IgG memory B cells were identified to be another potential correlate of protection against HuNoV gastroenteritis. We assessed B-cell responses following intramuscular administration of a bivalent (genogroup I, genotype 1 [GI.1]/genogroup II, genotype 4 [GII.4]) VLP vaccine using protocols identical to those used to evaluate cellular immunity following experimental GI.1 HuNoV infection. The kinetics and magnitude of cellular immunity to G1.1 infection were compared to those after VLP vaccination. Intramuscular immunization with the bivalent VLP vaccine induced the production of antibody-secreting cells (ASCs) and memory B cells. ASC responses peaked at day 7 after the first dose of vaccine and returned to nearly baseline levels by day 28. Minimal increases in ASCs were seen after a second vaccine dose at day 28. Antigen-specific IgG memory B cells persisted at day 180 postvaccination for both GI.1 and GII.4 VLPs. The overall trends in B-cell responses to vaccination were similar to the trends in the responses to infection, where there was a greater bias of an ASC response toward IgA and a memory B-cell response to IgG. The magnitude of the ASC and memory B-cell responses to the GI.1 VLP component of the vaccine was also comparable to that of the responses following GI.1 infection. The production of IgG memory B cells and persistence at day 180 is a key finding and underscores the need for future studies to determine if IgG memory B cells are a correlate of protection following vaccination. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168401.)

Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations

Intradermal (ID) BCG injection provides incomplete protection against TB in humans and experimental models. Alternative BCG vaccination strategies may improve protection in model species, including rhesus macaques. This study compares the immunogenicity and efficacy of BCG administered by ID and intravenous (IV) injection, or as an intratracheal mucosal boost (ID + IT), against aerosol challenge with Mycobacterium tuberculosis Erdman strain. Disease pathology was significantly reduced, and survival improved, by each BCG vaccination strategy, relative to unvaccinated animals. However, IV induced protection surpassed that achieved by all other routes, providing an opportunity to explore protective immunological mechanisms using antigen-specific IFN-γ ELISpot and polychromatic flow cytometry assays. IFN-γ spot forming units and multifunctional CD4 T-cell frequencies increased significantly following each vaccination regimen and were greatest following IV immunisation. Vaccine-induced multifunctional CD4 T-cells producing IFN-γ and TNF-α were associated with reduced disease pathology following subsequent M.tb challenge; however, high frequencies of this population following M.tb infection correlated with increased pathology. Cytokine producing T-cells primarily occupied the CD4 transitional effector memory phenotype, implicating this population as central to the mycobacterial response, potentially contributing to the stringent control observed in IV vaccinated animals. This study demonstrates the protective efficacy of IV BCG vaccination in rhesus macaques, offering a valuable tool for the interrogation of immunological mechanisms and potential correlates of protection.

Utility, limitations, and future of non-human primates for dengue research and vaccine development.

Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately, there are no licensed dengue vaccines available or specific anti-viral drugs. The development of a dengue vaccine faces unique challenges. The four serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, non-human primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article, we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally, we propose some guidelines toward a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups.

IL-32 is a molecular marker of a host defense network in human tuberculosis.

Tuberculosis is a leading cause of infectious disease-related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ- and IL-15-induced "defense response" genes. IL-32 induced the vitamin D-dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15-induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15-induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.

Developing a dengue vaccine: progress and future challenges

Dengue is an expanding public health problem in the tropics and subtropical areas. Millions of people, most from resource-constrained countries, seek treatment every year for dengue-related disease. Despite more than 70 years of effort, a safe and efficacious vaccine remains unavailable. Antidengue antiviral drugs also do not exist despite attempts to develop or repurpose drug compounds. Gaps in the knowledge of dengue immunology, absence of a validated animal or human model of disease, and suboptimal assay platforms to measure immune responses following infection or experimental vaccination are obstacles to drug and vaccine development efforts. The limited success of one vaccine candidate in a recent clinical endpoint efficacy trial challenges commonly held beliefs regarding potential correlates of protection. If a dengue vaccine is to become a reality in the near term, vaccine developers should expand development pathway explorations beyond those typically required to demonstrate safety and efficacy.

Norovirus virus-like particle vaccines for the prevention of acute gastroenteritis

Noroviruses (NoVs) are the most common cause of nonbacterial acute gastroenteritis in humans worldwide. These highly infectious viruses were, until recently, commonly thought to cause a mild, self-limiting disease in healthy individuals, but increasing epidemiology shows that the incidence and severity of illness due to NoV infection is substantial and similar to diseases where immunization is widely recommended. Human NoV challenge studies have identified carbohydrate histo-blood group antigen expression as an important human susceptibility factor for many strains and correspondingly, that antibodies which block carbohydrate virus binding represent a potential correlate of protection against NoV infection and illness. Since human NoVs do not replicate in cell culture, there are numerous challenges to the development of a vaccine to prevent illness or infection. However, the development of NoV virus-like particles (VLPs) has enabled significant progress toward effective vaccine candidates designed to protect against multiple circulating NoV strains. Vaccination with NoV VLP vaccines has been shown to both induce antibodies that block virus-derived VLP carbohydrate binding and protect against homologous viral challenge in a human clinical study.

A Comparative Analysis of Polyfunctional T Cells and Secreted Cytokines Induced by Bacille Calmette-Guérin Immunisation in Children and Adults

BCG vaccine is one of the most commonly-administered vaccines worldwide. Studies suggest the protective efficacy of BCG against TB is better for children than for adults. One potential explanation is that BCG induces a better protective immune response in children. Twenty six children and adults were immunised with BCG. The proportion of Th1-cytokine-producing mycobacterial-specific T cells, and the concentrations of secreted cytokines, were measured before and 10 weeks after BCG immunisation. A significant increase in the proportion of mycobacterial-specific cytokine-producing T cells was observed in both age groups. After BCG immunisation, children and adults had comparable proportions of mycobacterial-specific polyfunctional CD4 T cells when measured relative to the total number of CD4 T cells. However, relative to the subset of Th-1-cytokine-producing CD4 T cells, the proportion of polyfunctional cells was greater in children. Concentrations of secreted cytokines were comparable in children and adults. These findings suggest that the mycobacterial-specific cell-mediated immune response induced by BCG immunisation in children and adults is similar. The implication of a shift to a more polyfunctional immune response within the Th1-cytokine-producing CD4 T cells in children is uncertain as this aspect of the immune response has not been assessed as a potential correlate of protection against TB.

Immune Responses to Rotavirus Infection and Vaccination and Associated Correlates of Protection

Group A rotavirus (RV) strains are a major cause of acute gastroenteritis (AGE) in infants and young children worldwide [1]. RV disease accounts for more than one-third of all diarrhea-related hospitalizations and 500,000–600,000 deaths per year [2–4]; most deaths occur in sub-Saharan Africa and Asia [3, 4]. Direct medical and indirect annual costs associated with RV disease are estimated to be €400 million in Europe [5–7] and to exceed US$ 1 billion in the United States [8]. RV strains form a genus of the Reoviridae family and possess a genome of 11 segments of double-stranded (ds) RNA, encoding 6 structural viral proteins (VPs) and 6 nonstructural proteins (NSPs). The infectious particle (ie, virion) consists of 3 layers: the inner layer (core) contains the viral genome, the viral RNA-dependent RNA polymerase (RdRp, VP1), the capping enzyme (VP3), and the scaffolding protein (VP2); the core is surrounded by a middle layer (VP6), and the outer layer consists of VP7 and VP4 [9]. RV infects mature enterocytes in the small intestine. Viral replication leads to increased intracellular Ca2+ level (effected by NSP4), increased Cl- secretion, and shut-off of host cell protein synthesis (effected by NSP3), resulting in acute osmotic and secretory diarrhea (described in [9]). Various RV genes have been implicated in the pathogenesis of AGE [10]. After RV infection, a viremic stage of, at present, unclear significance has been identified in humans and experimental animals [11–13]. The RV-encoded NSP1 blocks interferon (IFN) production by various pathways [14–17]. RV infection down-regulates the IFN- and pro-inflammatory cytokine–associated pathways in calves [18]. RV strains have a high genomic and antigenic diversity and are classified into at least 7 different groups (A–G), distinguished by different VP6. Most human RV infections are caused by group A RV strains, which are further subdivided into at least 2 subgroups (I, II), 23 G types (determined by VP7, a glycoprotein), and 31 P types (determined by VP4, a protease-sensitive protein) [9, 19–21]. RV strains with different G and P types cocirculate and change in geographical regions over time [22–25]. In temperate climate regions, most cocirculating RV strains are types G1–G4 and G9 (typically G1P1A[8], G2P1B[4], G3P1A[8], G4P1A[8], and G9P1A[8]), but other G types (G5, G8, G10, and G12), in combination with various P types, may be most prevalent in tropical areas [21, 23, 24]. Nonspecific (innate) and acquired virus-specific humoral and cellular immune responses are elicited by RV infection [26, 27] or RV vaccination [28–33]. Although currently licensed vaccines are highly efficacious in protecting children from severe RV AGE, the molecular mechanisms of protection are not fully understood. This article considers the immune responses to natural RV infection and RV vaccination in both experimental animals and humans as potential correlates of protection.

Genomic Analysis Reveals Pre- and Postchallenge Differences in a Rhesus Macaque AIDS Vaccine Trial: Insights into Mechanisms of Vaccine Efficacy

We have employed global transcriptional profiling of whole blood to identify biologically relevant changes in cellular gene expression in response to alternative AIDS vaccine strategies with subsequent viral challenge in a rhesus macaque vaccine model. Samples were taken at day 0 (prechallenge), day 14 (peak viremia), and week 12 (set point) from animals immunized with replicating adenovirus type 5 host range (Ad5hr) recombinant viruses expressing human immunodeficiency virus HIV(env)(89.6P), simian immunodeficiency virus SIV(gag)(239), or SIV(nef)(239) alone or in combination with two intramuscular boosts with HIV(89.6P)gp140ΔCFI protein (L. J. Patterson et al., Virology 374:322-337, 2008), and each treatment resulted in significant control of viremia following simian-human immunodeficiency virus SHIV(89.6P) challenge (six animals per group plus six controls). At day 0, 8 weeks after the last treatment, the microarray profiles revealed significant prechallenge differences between treatment groups; data from the best-protected animals led to identification of a network of genes related to B cell development and lymphocyte survival. At peak viremia, expression profiles of the immunized groups were extremely similar, and comparisons to control animals reflected immunological differences other than effector T cell functions. Suggested protective mechanisms for vaccinated animals included upregulation of interleukin-27, a cytokine known to inhibit lentivirus replication, and increased expression of complement components, which may synergize with vaccine-induced antibodies. Divergent expression profiles at set point for the immunized groups implied distinct immunological responses despite phenotypic similarities in viral load and CD4(+) T cell levels. Data for the gp140-boosted group provided evidence for antibody-dependent, cell-mediated viral control, whereas animals immunized with only the replicating Ad5hr recombinants exhibited a different evolution of the B cell compartment even at 3 months postchallenge. This study demonstrates the sensitivity and discrimination of gene expression profiling of whole blood as an analytical tool in AIDS vaccine trials, providing unique insights into in vivo mechanisms and potential correlates of protection.

In this issue

AbstractCover imageThis issue's cover image depicts thymus ontogeny in mice associated with changes in the distribution patterns of Spatial and keratins by thymic epithelial cells, taken from Saade et al. (pp. 530–538). In this article, the authors explore the expression of the Spatial gene during thymus ontogeny and in the adult thymus, and demonstrate that in the medulla RANK signals regulate Spatial expression through the transcription factor Aire. Images were acquired with the Leica TCS SP5. magnified imageWorms get hormonalpp. 406–416Infections with parasitic helminths have been very informative when it comes to developing our understanding of Th2 immunity at mucosal sites. Although many researchers observe gender‐dependent differences in immune responsiveness, few have studied this phenomenon mechanistically. In this issue, Hepworth et al. investigate the role of sex hormones during the development of Th2 immunity to infection with the gastrointestinal nematode Trichuris muris. Interestingly, the authors show that androgens (such as testosterone) but not estrogens potently suppress the generation of protective Th2 immunity. This study identifies a complex interplay between the immune system and the host factors, such as hormones, and demonstrates that effective immunity can be profoundly influenced under such conditions. magnified imageProtective immunity in tuberculosis – not without IL‐18pp. 396–405On the 25th anniversary of γδ T cells' accidental discovery, γδ T cells remain poorly understood; however, the potent anti‐tumor and pro‐inflammatory functions of γδ T cells are well documented. In this issue, to further explore the interaction of γδ T cells with other components of the immune system, Gonçalves‐Sousa et al. show that mouse Treg efficiently suppress γδ T cell responses both in vitro and in vivo. Treg use cell‐to‐cell contact to “anergize” γδ T cells, thus preventing their cytotoxicity and cytokine (IFN‐γ, IL‐17) secretion functions upon activation. This suppression, however, can be partially reversed using anti‐GITR antibodies, which may be relevant for clinical application. In fact, as human Treg have also been shown to inhibit γδ T cell responses to TB antigens, the combined modulation of γδ and Treg functions should be considered in future immunotherapeutic protocols. magnified imageMeasles virus‐specific T cells: Kill or be killedpp. 388–395Measles is a highly contagious viral disease, killing approximately 200 000 children each year. The virus is lymphotropic and infects high percentages of B and T cells via its cellular receptor CD150. Paradoxically, virus‐specific T cells can be either viral targets or effector cells mediating viral clearance. In this issue, de Vries et al. examine whether specific CD4+ or CD8+ T cells can inhibit measles virus replication. The authors infected B cells with a recombinant measles virus expressing GFP, added specific T cells and monitored virus dissemination. Using this model, the authors demonstrate that measles virus‐specific CD8+ T‐cell clones and primary CD8+ T cells isolated from convalescent measles patients suppressed virus replication in autologous or HLA‐matched B cells. Specific CD4+ T cells not only were incapable of inhibiting virus replication, but were also more readily infected by the virus. The authors speculate that a similar approach may be used to study functional T‐cell responses as potential correlates of protection in vaccine trials. magnified imageA new drug for modulating T‐cell differentiation in autoimmune conditionspp. 460–469Natura‐alpha is a newly developed immune‐regulatory agent that has been shown to exert potent therapeutic activity against colitis in the murine model. In this issue, Glatigny et al. study the effects of Natura‐alpha on collagen‐induced arthritis, a murine model that mimics many of the symptoms of rheumatoid arthritis. The authors examine the effect of the compound on both adaptive and humoral immune responses. Although the exact effects of the compound on T‐helper differentiation pathways remain to be elucidated, this study suggests that Natura‐alpha modulates autoimmune inflammation by targeting the Th1/Th17 pathway. This study implies that the effects of Natura‐alpha may also extend to other autoimmune diseases involving Th1/Th17 cells. magnified imagep53, a double‐edged sword in the fight against cancerpp. 559–568Among the many conundrums that face immunologists is the fact that many pro‐apoptoic molecules that suppress tumour development, also repress the generation of T‐cell responses that are needed for effective anti‐tumour immunity. Therefore, while a lack of apoptotic machinery on the one hand promotes tumoroigenesis, on the other it also has the potential to help generate enhanced T‐cell responses against tumors. In this issue, Singh et al. report that unlike wild‐type T cells, T cells lacking the tumor suppressor p53 do not undergo apoptosis when the TCR is engaged in the absence of costimulation. Furthermore, p53−/− mice mount an effective and potent cytotoxic T‐cell response against transplanted tumors and successfully clear the tumour. Thus, p53 functions not only as a tumor suppressor but also as an opposing role in dampening T‐cell responses, and thus preventing the generation of effective anti‐tumor T‐cell immunity. This study suggests that manipulation of p53 for cancer therapy requires a careful balancing act. magnified image

Evaluation of Circulating Intestinally Committed Memory B Cells in Children Vaccinated with Attenuated Human Rotavirus Vaccine

In a double blind trial, 319 fully immunized children received two doses of either placebo or 10(6.7) focus-forming units of the attenuated RIX4414 human rotavirus (RV) vaccine ("all-in-one" formulation). Plasma RV-specific IgA (RV IgA), stool RV IgA, and circulating total and RV memory B cells (CD19+ IgD+/- CD27+) with an intestinal homing phenotype (alpha4beta7+ CCR9+/-) were measured, after the first and second doses, as potential correlates of protection. After the first and/or second dose, 54% of vaccinees and 13% of placebo recipients had plasma RV IgA. Before vaccination, most (95%) of the children (of both study groups) were breast-fed and had stool RV IgA (68.64%). Coproconversion (4-fold increase) after the first and/or second dose was observed in 32.7% of vaccinees and 17.4% of placebo recipients. No significant difference was seen when comparing the frequencies of any subset of memory B cells between vaccinees and placebo recipients. Statistically significant weak correlations were found between plasma RV IgA titers and coproconversion, and several subsets of memory B cells. The vaccine provided 74.8% protection (95% confidence interval, 30.93-92.62) against any RV gastroenteritis and 100% protection (95% confidence interval, 14.53-100) against severe RV gastroenteritis. When vaccinees and placebo recipients were considered together, a correlation was found between protection from disease and plasma RV IgA measured after dose 2 and RV memory (IgD- CD27+ alpha4beta7+ CCR9+) circulating B cells measured after dose 1. However, the correlation coefficients for both tests were low (<0.2), suggesting that other factors are important in explaining protection from disease.

CD8+ lymphocyte antiviral activity in monkeys immunized with SIV recombinant poxvirus vaccines: potential role in vaccine efficacy.

Protection against intravenous simian immunodeficiency virus (SIV) challenge was assessed in rhesus macaques after immunization with a highly attenuated vaccinia (NYVAC)-SIV recombinant. One-third of vaccinated animals controlled viral infection and progressed to disease more slowly than control animals (Benson J, et al.: J Virol 1998;72:4170). However, this protection was not associated with neutralizing antibodies, cytotoxic T lymphocytes, or helper T cell responses. To explore other potential correlates of protection, we examined CD8+ T cell antiviral activity in macaques vaccinated with NYVAC-SIV, with or without added cytokine adjuvants, and in controls receiving only IL-12 or IL-12 plus IL-2. Before immunization, naive macaques exhibited a broad range of CD8+ T cell antiviral activity. Nevertheless, in the course of immunization, the vaccinated macaques as a group developed increased CD8+ T cell antiviral activity while the controls remained stable. Infectious SIV exposure also increased antiviral activity. Prechallenge antiviral activity levels of vaccinated macaques were not sufficient to prevent SIV transmission or control viral replication during acute infection. However, vaccinated animals consistently exhibited reduced viral loads postchallenge compared with controls. Moreover, high suppressive activity 8 weeks postchallenge, at which time the viremia set point was established, was significantly correlated with reduced viral load and slow disease progression. Prechallenge antiviral activity influenced this result, as decreased viremia and slow progressor status were more apparent in macaques with high suppressive activity both pre- and postchallenge. Our data demonstrate the impact of CD8+ antiviral activity on viral replication and disease progression, and suggest that vaccine designs able to elicit high levels of this activity will contribute significantly to protective efficacy.

HIV infection and pathogenesis: what about chemokines?

Several chemotactic cytokines, or chemokines. inhibit HIV replication by blocking or down regulating chemokine receptors that serve as entry cofactors for the virus. Although the role of chemokine receptors in HIV pathogenesis has been the subject of intense interest, chemokines are comparatively less seriously considered as potential correlates of protection from HIV infection and disease progression. However, a critical analysis of newly available data reveals substantial evidence to support a beneficial role for chemokines in HIV infection and disease. In this review we summarize the results of such studies and their promising implications for HIV infection.