Most CD4+ T cells from human immunodeficiency virus-1 infected patients can undergo prolonged clonal expansion

We have addressed the capacity of HIV-1 infection to alter the growth of primary CD4+ T cells, but at the clonal level. Single T cells were expanded in the presence of PHA, IL-2, and small numbers of accessory dendritic cells. We report two new findings. First, T cells from seropositive individuals, even those with AIDS and markedly reduced CD4+ counts, exhibit a normal cloning efficiency, and proliferative capacity. This result is in contrast to two prior reports of a low cloning efficiency in CD4+ T cells from HIV-1-infected patients. Second, when we added high doses of exogenous HIV-1 to T cell clones from control subjects, we observed infection but not cytotoxity or loss of CD4+ cells, following addition of virus stocks at days 0, 3, and/or 7 of clonal growth. The same HIV-1 isolates markedly reduced CD4+ T cells in bulk mononuclear cultures. When tested at day 11, HIV-1 mRNA was expressed in some cells of exogenously infected clones by in situ hybridization; when tested at day 18, several clones could transactivate a TAT-sensitive cell line. These findings suggest that the loss of CD4+ T cells in infected individuals is not the inevitable result of the activation of latent infection, or spread of a productive infection, during clonal growth

Latent HIV-1 infection in enriched populations of blood monocytes and T cells from seropositive patients

The extent of latent HIV-1 infection in blood T cells and monocytes of 23 seropositive individuals was examined using DNA amplification (PCR) of HIV-1 sequences. Amplified DNA was found in at least one cell type in all seropositives tested, including 13 asymptomatic, 5 ARC, and 5 AIDS patients. Amplification with two or more primer sets from the gag, env, LTR occurred in 21 (91%) patients\u27 T cells and 17 (74%) patients\u27 monocytes. However, amplification with the LTR primers n monocytes was uncommon. Among four patients tested, amplified DNA continued to be detected after a greater than one thousand-fold dilution (\u3c 500 cells) of both T cell and monocyte lysates. Repeat analysis after 7-9 mo in five seropositives yielded similar findings in T cells and monocytes, but some variation in the efficacy of amplification with individual primers occurred. There was no difference in those 10 patients who were taking AZT, compared to those who were untreated. Our results indicate that a fraction (\u3c 1%) of both T cells and monocytes in blood carry a latent infection in all stages of HIV-1 disease and can serve as reservoirs throughout AZT therapy

Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition : implications for active and passive immunization.

CAPRISA, 2016.Abstract available in PDF file

Association of T Cell Proliferative Responses and Phenotype with Virus Control in Chronic Progressive HIV-1 Disease

The role of T cell immunity in virus control during chronic infection was examined in 79 human immunodeficiency virus type 1 (HIV-1)-infected subjects randomized to receive antiretroviral therapy. HIV-1 p24-specific responses were detected in 20% of the subjects at baseline, increasing to 28% of the subjects at weeks 16-24. Induction of virologic suppression was associated with lower plasma HIV-1 RNA levels and a higher percentage of Fas+ CD8+ T cells at baseline, whereas maintenance of suppression was associated with higher CD4+ T cell counts and, marginally, with a higher percentage of Fas+ CD4+ T cells at weeks 16-24. These findings indicate that Fas coexpression on T cells, in addition to plasma HIV-1 RNA levels and CD4+ T cell counts, may predict virologic outcom

Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study.

Background. The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C. Methods. We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725. Findings. 801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76–2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20 483 copies per mL (n=33) in the vaccine group and 34 032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens. Interpretation. The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine

Defining the risk of SARS-CoV-2 variants on immune protection

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures

Defining the risk of SARS-CoV-2 variants on immune protection.

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures

The Transformation of Social Institutions in the North American Southeast

Corporate institutions, which transformed in the American Southeast over some 14,000 years, include social heterarchies and hierarchies that arose within the institutional contexts of descent groups, ritual sodalities, and social houses. The strategic and tactical actions of competitive and cooperative agents contributed to differing expressions of organizational changes through a variety of forms, including feasting, feuding/warfare, inalienable goods circulation, indebtedness, monumental constructions, mortuary events, processions/rogations, strategic marriages, and additional ritual and social practices. The nexus of social institutions that evolved along these pathways served as a catalyst for social changes, including the ways through which social institutions became transformed. Such social processes inform archaeologists of the agency, organization, and practice of people who not only invented and manipulated cosmologies, ideologies, institutions, and resources to achieve varying degrees of inequality, power, and wealth, but also those who resisted the efforts of aggrandizers. The author’s arguments focus on aristocratic social actions and actors, and the practices that enabled them to gain power and wealth through exclusive and restrictive corporate institutions