Validation of dried blood spots for capturing hepatitis C virus diversity for genomic surveillance.

Dried blood spots (DBS) have emerged as a promising alternative to traditional venous blood for hepatitis C virus (HCV) testing. However, their capacity to accurately reflect the genetic diversity of HCV remains poorly understood. We employed deep sequencing and advanced phylogenetic analyses on paired plasma and DBS samples from two common subtypes to evaluate the suitability of DBS for genomic surveillance. Results demonstrated that DBS captured equivalent viral diversity compared to plasma with no phylogenetic discordance observed. The ability of DBS to accurately reflect the profile of viral genetic diversity suggests it may be a promising avenue for future surveillance efforts to curb HCV outbreaks.

Emergence of Novel Norovirus GII.4 Variant.

We detected a novel GII.4 variant with an amino acid insertion at the start of epitope A in viral protein 1 of noroviruses from the United States, Gabon, South Africa, and the United Kingdom collected during 2017-2022. Early identification of GII.4 variants is crucial for assessing pandemic potential and informing vaccine development.

Validation of Dried Blood Spots for Capturing Hepatitis C Virus Diversity for Genomic Surveillance.

Dried blood spots (DBS) have emerged as a promising alternative to traditional venous blood for HCV testing. However, their capacity to accurately reflect the genetic diversity of HCV remains poorly understood. We employed deep sequencing and advanced phylogenetic analyses on paired plasma and DBS samples to evaluate the suitability of DBS for genomic surveillance. Results demonstrated that DBS captured equivalent viral diversity compared to plasma with no phylogenetic discordance observed. The ability of DBS to accurately reflect the profile of viral genetic diversity suggests it may be a promising avenue for future surveillance efforts to curb HCV outbreaks.

Inferring the multiplicity of founder variants initiating HIV-1 infection: a systematic review and individual patient data meta-analysis.

BACKGROUND: HIV-1 infections initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis than those initiated with single founder variants, yet little is known about the routes of exposure through which transmission of multiple founder variants is most probable. Here we used individual patient data to calculate the probability of multiple founders stratified by route of HIV exposure and study methodology. METHODS: We conducted a systematic review and meta-analysis of studies that estimated founder variant multiplicity in HIV-1 infection, searching MEDLINE, Embase, and Global Health databases for papers published between Jan 1, 1990, and Sept 14, 2020. Eligible studies must have reported original estimates of founder variant multiplicity in people with acute or early HIV-1 infections, have clearly detailed the methods used, and reported the route of exposure. Studies were excluded if they reported data concerning people living with HIV-1 who had known or suspected superinfection, who were documented as having received pre-exposure prophylaxis, or if the transmitting partner was known to be receiving antiretroviral treatment. Individual patient data were collated from all studies, with authors contacted if these data were not publicly available. We applied logistic meta-regression to these data to estimate the probability that an HIV infection is initiated by multiple founder variants. We calculated a pooled estimate using a random effects model, subsequently stratifying this estimate across exposure routes in a univariable analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the exposure routes. This study is registered with PROSPERO, CRD42020202672. FINDINGS: We included 70 publications in our analysis, comprising 1657 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0·25 (95% CI 0·21-0·29), with moderate heterogeneity (Q=132·3, p<0·0001, I2=64·2%). Our multivariable analysis uncovered differences in the probability of multiple variant infection by exposure route. Relative to a baseline of male-to-female transmission, the predicted probability for female-to-male multiple variant transmission was significantly lower at 0·13 (95% CI 0·08-0·20), and the probabilities were significantly higher for transmissions in people who inject drugs (0·37 [0·24-0·53]) and men who have sex with men (0·30 [0·33-0·40]). There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0·21 [0·14-0·31]), post-partum transmission (0·18 [0·03-0·57]), pre-partum transmission (0·17 [0·08-0·33]), and intra-partum transmission (0·27 [0·14-0·45]). INTERPRETATION: We identified that transmissions in people who inject drugs and men who have sex with men are significantly more likely to result in an infection initiated by multiple founder variants, and female-to-male infections are significantly less probable. Quantifying how the routes of HIV infection affect the transmission of multiple variants allows us to better understand how the evolution and epidemiology of HIV-1 determine clinical outcomes. FUNDING: Medical Research Council Precision Medicine Doctoral Training Programme and a European Research Council Starting Grant.

Identification of Genetically Related HCV Infections Among Self-Described Injecting Partnerships.

BACKGROUND: The current opioid epidemic across the United States has fueled a surge in the rate of new hepatitis C virus (HCV) infections among young persons who inject drugs (PWIDs). Paramount to interrupting transmission is targeting these high-risk populations and understanding the underlying network structures facilitating transmission within these communities. METHODS: Deep sequencing data were obtained for 52 participants from 32 injecting partnerships enrolled in the U-Find-Out (UFO) Partner Study, which is a prospective study of self-described injecting dyad partnerships from a large community-based study of HCV infection in young adult PWIDs from San Francisco. Phylogenetically linked transmission events were identified using traditional genetic-distance measures and viral deep sequence phylogenies reconstructed to determine the statistical support of inferences and the direction of transmission within partnerships. RESULTS: Using deep sequencing data, we found that 12 of 32 partnerships were genetically similar and clustered. Three additional phylogenetic clusters were found describing novel putative transmission links outside of the injecting relationship. Transmission direction was inferred correctly for 5 partnerships with the incorrect transmission direction inferred in more than 50% of cases. Notably, we observed that phylogenetic linkage was most often associated with a lower number of network partners and involvement in a sexual relationship. CONCLUSIONS: Deep sequencing of HCV among self-described injecting partnerships demonstrates that the majority of transmission events originate from outside of the injecting partnership. Furthermore, these findings caution that phylogenetic methods may be unable to routinely infer the direction of transmission among PWIDs especially when transmission events occur in rapid succession within high-risk networks.

Prevalence of transmitted HIV-1 drug resistance among treatment-naive individuals in China, 2000-2016.

Human immunodeficiency virus (HIV) with transmitted drug-resistance (TDR) limits the therapeutic options available for treatment-naive HIV patients. This study aimed to further our understanding of the prevalence and transmission characteristics of HIV with TDR for the application of first-line antiretroviral regimens. A total of 6578 HIV-1 protease/reverse-transcriptase sequences from treatment-naive individuals in China between 2000 and 2016 were obtained from the Los Alamos HIV Sequence Database and were analyzed for TDR. Transmission networks were constructed to determine genetic relationships. The spreading routes of large TDR clusters were identified using a Bayesian phylogeographic framework. TDR mutations were detected in 274 (4.51%) individuals, with 1.40% associated with resistance to nucleoside reverse transcriptase inhibitors, 1.52% to non-nucleoside reverse transcriptase inhibitors, and 1.87% to protease inhibitors. The most frequent mutation was M46L (58, 0.89%), followed by K103N (36, 0.55%), M46I (36, 0.55%), and M184V (26, 0.40%). The prevalence of total TDR initially decreased between 2000 and 2010 (OR = 0.83, 95% CI 0.73-0.95) and then increased thereafter (OR = 1.50, 95% CI 1.13-1.97). The proportion of sequences in a cluster (clustering rate) among HIV isolates with TDR sequences was lower than that of sequences without TDR (40.5% vs. 48.8%, P = 0.023) and increased from 27.3% in 2005-2006 to 63.6% in 2015-2016 (P < 0.001). While most TDR mutations were associated with reduced relative transmission fitness, mutation M46I was associated with higher relative transmission fitness than the wild-type strain. This study identified a low-level prevalence of TDR HIV in China during the last two decades. However, the increasing TDR HIV rate since 2010, the persistent circulation of drug resistance mutations, and the expansion of self-sustaining drug resistance reservoirs may compromise the efficacy of antiretroviral therapy programs.

Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.

Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans.

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England.

A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in September 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modeling approaches, we estimate that this variant has a 43 to 90% (range of 95% credible intervals, 38 to 130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine rollout, COVID-19 hospitalizations and deaths across England in the first 6 months of 2021 were projected to exceed those in 2020. VOC 202012/01 has spread globally and exhibits a similar transmission increase (59 to 74%) in Denmark, Switzerland, and the United States.

Hepatitis C Virus Transmission Clusters in Public Health and Correctional Settings, Wisconsin, USA, 2016-20171.

Ending the hepatitis C virus (HCV) epidemic requires stopping transmission among networks of persons who inject drugs. Identifying transmission networks by using genomic epidemiology may inform community responses that can quickly interrupt transmission. We retrospectively identified HCV RNA-positive specimens corresponding to 459 persons in settings that use the state laboratory, including correctional facilities and syringe services programs, in Wisconsin, USA, during 2016-2017. We conducted next-generation sequencing of HCV and analyzed it for phylogenetic linkage by using the Centers for Disease Control and Prevention Global Hepatitis Outbreak Surveillance Technology platform. Analysis showed that 126 persons were linked across 42 clusters. Phylogenetic clustering was higher in rural communities and associated with female sex and younger age among rural residents. These data highlight that HCV transmission could be reduced by expanding molecular-based surveillance strategies to rural communities affected by the opioid crisis.

Early prediction of mortality risk among patients with severe COVID-19, using machine learning.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 infection, has been spreading globally. We aimed to develop a clinical model to predict the outcome of patients with severe COVID-19 infection early. METHODS: Demographic, clinical and first laboratory findings after admission of 183 patients with severe COVID-19 infection (115 survivors and 68 non-survivors from the Sino-French New City Branch of Tongji Hospital, Wuhan) were used to develop the predictive models. Machine learning approaches were used to select the features and predict the patients' outcomes. The area under the receiver operating characteristic curve (AUROC) was applied to compare the models' performance. A total of 64 with severe COVID-19 infection from the Optical Valley Branch of Tongji Hospital, Wuhan, were used to externally validate the final predictive model. RESULTS: The baseline characteristics and laboratory tests were significantly different between the survivors and non-survivors. Four variables (age, high-sensitivity C-reactive protein level, lymphocyte count and d-dimer level) were selected by all five models. Given the similar performance among the models, the logistic regression model was selected as the final predictive model because of its simplicity and interpretability. The AUROCs of the external validation sets were 0.881. The sensitivity and specificity were 0.839 and 0.794 for the validation set, when using a probability of death of 50% as the cutoff. Risk score based on the selected variables can be used to assess the mortality risk. The predictive model is available at [https://phenomics.fudan.edu.cn/risk_scores/]. CONCLUSIONS: Age, high-sensitivity C-reactive protein level, lymphocyte count and d-dimer level of COVID-19 patients at admission are informative for the patients' outcomes.

Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.

Evolutionary characteristics and genetic transmission patterns of predominant HIV-1 subtypes among men who have sex with men in China.

OBJECTIVES: Men who have sex with men (MSM) represent one of the major risk groups for HIV-1 infection in China, and the predominant subtypes among this population has changed over the last two decades. The objective of this study was to determine the evolutionary characteristics and transmission patterns of the dominant HIV-1 strains in the Chinese MSM population. METHODS: A total of 4980 published HIV-1 pol gene sequences from MSM in China were retrieved and comprehensive evolutionary and transmission analyses were then conducted. Bayesian coalescent-based methods and selection pressure analyses were used to reconstruct the time-scale and demographic history and to estimate other evolutionary parameters. Transmission patterns were characterized using network analyses. RESULTS: There were 2546 (51.12%) CRF01_AE, 1263 (25.36%) CRF07_BC, and 623 (12.51%) subtype B, accounting for 88.99% of the total sequences. From 2000 to 2016, the prevalence of CRF01_AE was stable, comprising nearly half of all sequences over time (58.33-45.38%, p=0.071). CRF07_BC increased slightly from 13.3% to 22.49% (p<0.001), while subtype B decreased dramatically from 41.67% to 9.04% (p<0.001). Demographic reconstruction showed that the greatest expansion of the HIV epidemic occurred between 1999 and 2005. CRF01_AE had a higher estimated evolutionary rate (2.97×10-3 substitutions/site/year) and exhibited more sites under positive selection (25/351 codons) compared to the other subtypes. Network analyses showed that CRF07_BC (68.29%, 84/123) had a higher proportion of cross-region networks than CRF01_AE (49.1%, 174/354) and subtype B (36.46%, 35/96) (p<0.001). CONCLUSIONS: The predominant subtypes of HIV-1 in Chinese MSM have different evolutionary characteristics and transmission patterns, which poses a significant challenge to HIV treatment and disease prevention.

Role of HCV Viremia in Corroborated HCV Transmission Events Within Young Adult Injecting Partnerships.

BACKGROUND: Hepatitis C virus (HCV), a major cause of morbidity and mortality, is common and rising among young persons who inject drugs (PWID). Reducing the level of viremia may be an intervention, yet the impact of viremia on HCV transmission is unknown. METHODS: We conducted a prospective study of injecting partnerships (Partner Study) of young adult (age < 30 years) PWID within the UFO Study, which enrolled those at risk for HCV or with seronegative viremic infection and up to 3 HCV RNA-positive regular injecting partners. We examined the level of HCV viremia and stage of infection in the HCV-positive partner in regression analyses of HCV transmission events that were corroborated via HCV phylogenetic linkage analyses. RESULTS: We enrolled 69 at-risk/acutely infected PWID. There were 25 new HCV infections (incidence rate, 35.9 per 100 person-years; 95% confidence interval [CI], 24.3-53.2 per 100 person-years); 12/25 (48%) were phylogenetically linked to at least 1 partner. We found no association between the infected partner's quantitative level of HCV viremia and likely transmission in multivariate analyses (adjusted odds ratio [AOR], 0.90; 95% confidence interval [CI], 0.55-1.46); however, seronegative viremic infection in the infected partner was associated with increased transmission (AOR, 28.02; 95% CI, 5.61-139.95). CONCLUSIONS: The HCV viremia level was not associated with increased odds of transmission, yet acute HCV infection (seronegative viremic) was. Explanations include high-risk behavior during acute infection or missed fluctuations in viremia during acute infection. Both point to the need for frequent testing to detect new infection and attempt to prevent onward transmission.

Lower Broadly Neutralizing Antibody Responses in Female Versus Male HIV-1 Infected Injecting Drug Users.

Understanding the factors involved in the development of broadly neutralizing antibody (bNAb) responses in natural infection can guide vaccine design aimed at eliciting protective bNAb responses. Most of the studies to identify and study the development of bNAb responses have been performed in individuals who had become infected via homo- or heterosexual HIV-1 transmission; however, the prevalence and characteristics of bNAb responses in injecting drug users (IDUs) have been underrepresented. We retrospectively studied the prevalence of bNAb responses in HIV-1 infected individuals in the Amsterdam Cohort, including 50 male and 35 female participants who reported injecting drug use as the only risk factor. Our study revealed a significantly lower prevalence of bNAb responses in females compared to males. Gender, transmission route and CD4+ count at set point, but not viral load, were independently associated with the development of bNAb responses in IDUs. To further explore the influences of gender in the setting of IDU, we also looked into the Swiss 4.5k Screen. There we observed lower bNAb responses in female IDUs as well. These results reveal that the emergence of bNAbs may be dependent on multiple factors, including gender. Therefore, the effect of gender on the development of bNAb responses is a factor that should be taken into account when designing vaccine efficacy trials.

Capturing sequence diversity in metagenomes with comprehensive and scalable probe design.

Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. Here we present CATCH, a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs optimal probe sets, with a specified number of oligonucleotides, that achieve full coverage of, and scale well with, known sequence diversity. We focus on applying CATCH to capture viral genomes in complex metagenomic samples. We design, synthesize, and validate multiple probe sets, including one that targets the whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriches unique viral content on average 18-fold, allowing us to assemble genomes that could not be recovered without enrichment, and accurately preserves within-sample diversity. We also use these probe sets to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of uncharacterized viral infections in human and mosquito samples. The results demonstrate that CATCH enables more sensitive and cost-effective metagenomic sequencing.

Metagenomic Sequencing of HIV-1 in the Blood and Female Genital Tract Reveals Little Quasispecies Diversity during Acute Infection.

Heterosexual transmission of human immunodeficiency virus type 1 (HIV-1) is associated with a significant bottleneck in the viral quasispecies population, yet the timing of that bottleneck is poorly understood. We characterized HIV-1 diversity in the blood and female genital tract (FGT) within 2 weeks after detection of infection in three women enrolled in a unique prospective cohort in South Africa. We assembled full-length HIV-1 genomes from matched cervicovaginal lavage (CVL) samples and plasma. Deep sequencing allowed us to identify intrahost single-nucleotide variants (iSNVs) and to characterize within-sample HIV-1 diversity. Our results demonstrated very little HIV-1 diversity in the FGT and plasma by the time viremia was detectable. Within each subject, the consensus HIV-1 sequences were identical in plasma and CVL fluid. No iSNV was present at >6% frequency. One subject had 77 low-frequency iSNVs across both CVL fluid and plasma, another subject had 14 iSNVs in only CVL fluid from the earliest time point, and the third subject had no iSNVs in CVL fluid or plasma. Overall, the small amount of diversity that we detected was greater in the FGT than in plasma and declined over the first 2 weeks after viremia was detectable, compatible with a very early HIV-1 transmission bottleneck. To our knowledge, our study represents the earliest genomic analysis of HIV-1 in the FGT after transmission. Further, the use of metagenomic sequencing allowed us to characterize other organisms in the FGT, including commensal bacteria and sexually transmitted infections, highlighting the utility of the method to sequence both HIV-1 and its metagenomic environment.IMPORTANCE Due to error-prone replication, HIV-1 generates a diverse population of viruses within a chronically infected individual. When HIV-1 is transmitted to a new individual, one or a few viruses establish the new infection, leading to a genetic bottleneck in the virus population. Understanding the timing and nature of this bottleneck may provide insight into HIV-1 vaccine design and other preventative strategies. We examined the HIV-1 population in three women enrolled in a unique prospective cohort in South Africa who were followed closely during the earliest stages of HIV-1 infection. We found very little HIV-1 diversity in the blood and female genital tract during the first 2 weeks after virus was detected in the bloodstream. These results are compatible with a very early HIV-1 population bottleneck, suggesting the need to study the HIV-1 population in the female genital tract before virus is detectable in the bloodstream.

Mamu-B*17+ Rhesus Macaques Vaccinated with env, vif, and nef Manifest Early Control of SIVmac239 Replication.

Certain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of "elite" control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I allele Mamu-B*17 Approximately 21% of Mamu-B*17+ and 50% of Mamu-B*08+ RMs control chronic-phase viremia after SIVmac239 infection. Because CD8+ T cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression in Mamu-B*08+ RMs, we investigated whether this might also be true for Mamu-B*17+ RMs. Two groups of Mamu-B*17+ RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together with env (group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlike Mamu-B*08+ RMs, preexisting SIV-specific CD8+ T cells alone do not facilitate long-term virologic suppression in Mamu-B*17+ RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to <15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control in Mamu-B*17+ RMs and implicate vaccine-induced, nonneutralizing anti-Env antibodies in the containment of immunodeficiency virus infection.IMPORTANCE A better understanding of the immune correlates of protection against HIV might facilitate the development of a prophylactic vaccine. Therefore, we investigated simian immunodeficiency virus (SIV) infection outcomes in rhesus macaques expressing the major histocompatibility complex class I allele Mamu-B*17 Approximately 21% of Mamu-B*17+ macaques spontaneously controlled chronic phase viremia after SIV infection, an effect that may involve CD8+ T cells targeting Mamu-B*17-restricted SIV epitopes. We vaccinated Mamu-B*17+ macaques with genes encoding immunodominant epitopes in Vif and Nef alone (group 1) or together with env (group 2). Although neither vaccine regimen prevented SIV infection, 5/8 group 2 vaccinees controlled viremia to below detection limits shortly after infection. This outcome, which was not observed in group 1, was associated with vaccine-induced, nonneutralizing Env-binding antibodies. Together, these findings suggest a limited contribution of Vif- and Nef-specific CD8+ T cells for virologic control in Mamu-B*17+ macaques and implicate anti-Env antibodies in containment of SIV infection.