Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment ...initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy at primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of suppressive therapy during chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed primarily during the initial 3 to 4 years of treatment. However, in patients who started antiretroviral therapy in early infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. HIV-1-specific T cell responses remained continuously detectable during antiretroviral therapy, independently of the timing of treatment initiation. Together, these data suggest that early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, but the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients good candidates for future interventional studies aiming at HIV-1 eradication and cure.
Antiretroviral therapy can effectively suppress HIV-1 replication to undetectable levels; however, HIV-1 can persist despite treatment, and viral replication rapidly rebounds when treatment is discontinued. This is mainly due to the presence of latently infected CD4 T cells, which are not susceptible to antiretroviral drugs. Starting treatment in the earliest stages of HIV-1 infection can limit the number of these latently infected cells, raising the possibility that these viral reservoirs are naturally eliminated if suppressive antiretroviral treatment is continued for extremely long periods of time. Here, we analyzed nine patients who started on antiretroviral therapy within the earliest weeks of the disease and continued treatment for more than 10 years. Our data show that early treatment accelerated the decay of infected CD4 T cells and led to very low residual levels of detectable HIV-1 after long-term therapy, levels that were otherwise detectable in patients who are able to maintain a spontaneous, drug-free control of HIV-1 replication. Thus, long-term antiretroviral treatment started during early infection cannot eliminate HIV-1, but the reduced reservoirs of HIV-1 infected cells in such patients may increase their chances to respond to clinical interventions aiming at inducing a drug-free remission of HIV-1 infection.
Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly ...neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-binding-site antibodies that mimic binding to CD4. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 immunoglobulin H (IgH) chain amino acids and arise independently from two related IgH genes. Comparison of the crystal structure of one of the antibodies to the broadly neutralizing antibody VRC01 revealed conservation of the contacts to the HIV spike.
The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism, lower expression on the cell surface, and more extensive ligand-receptor ...interactions with killer-cell immunoglobulin-like receptors. A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed -35) associates with control of HIV, and with levels of HLA-C messenger RNA transcripts and cell-surface expression, but the mechanism underlying its varied expression is unknown. We proposed that the -35 SNP is not the causal variant for differential HLA-C expression, but rather is marking another polymorphism that directly affects levels of HLA-C. Here we show that variation within the 3' untranslated region (UTR) of HLA-C regulates binding of the microRNA hsa-miR-148 to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape post-transcriptional regulation. The 3' UTR variant associates strongly with control of HIV, potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease.
The discovery of deep-sea hydrothermal vents in 1977 challenged our views of ecosystem functioning and yet, the research conducted at these extreme and logistically challenging environments still ...continues to reveal unique biological processes. Here, we report for the first time, a unique behavior where the deep-sea skate, Bathyraja spinosissima, appears to be actively using the elevated temperature of a hydrothermal vent environment to naturally "incubate" developing egg-cases. We hypothesize that this behavior is directly targeted to accelerate embryo development time given that deep-sea skates have some of the longest egg incubation times reported for the animal kingdom. Similar egg incubating behavior, where eggs are incubated in volcanically heated nesting grounds, have been recorded in Cretaceous sauropod dinosaurs and the rare avian megapode. To our knowledge, this is the first time incubating behavior using a volcanic source is recorded for the marine environment.
CD8+ T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed ...'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8+ T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes-such as BATF-that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.
... the peak level of p24 values was significantly lower in the EC-nef viruses than in the CP-nef viruses. Because Nef activity is highly dependent on PBMC donors, we tested 4 different donors' PBMC ...and compared the initial burst of their viral replication at Day 9.
HIV-1 elite controllers spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary computed tomography ...angiography (CTA) in elite controllers, nonelite controller, chronically HIV-1 infected, antiretroviral therapy (ART)-treated patients with undetectable viral load ('chronic HIV'), and HIV-negative controls. Prevalence of atherosclerosis (78 vs. 42%, P < 0.05) and markers of immune activation were increased in elite controllers compared with HIV-negative controls. sCD163, a monocyte activation marker, was increased in elite controllers compared with chronic HIV-1 (P < 0.05) and compared with HIV-negative controls (P < 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among elite controllers.
This study aimed to determine whether the insemination site and dose with cryopreserved sperm of reproductively normal mares affect the sperm population in uterine tubes and the intensity of ...endometrial inflammatory response. Experimental subjects were estrous mares inseminated, in the mid-uterine body (Body) or the tip of the uterine horn (Tip), ipsilateral to the dominant follicle, with one 0.5 mL straw with 50 × 106 sperm (50) or with eight straws with 50 × 106 sperm/straw (400). Mares were slaughtered 2 h, 4 h and 12 h after artificial insemination (AI) and randomly assigned to following groups: Body 50 (n = 19) (2 h, 4 h or 12 h); Tip 50 (n = 29) (2 h, 4 h, or 12 h); Body 400 (n = 24) (2 h, 4 h, or 12 h); Tip 400 (n = 21) (2 h, 4 h, or 12 h). A Control group (n = 16) was not inseminated. After slaughter, uterine tubes were separated from uterus, and uteri and tubes flushed with phosphate-buffered saline (PBS). After flushing, an endometrial sample was collected from ipsilateral and contralateral horns and mid-uterus body for further histopathological examination. A sample of each uterine tube flushing was examined for sperm count, and a sample of each uterine flushing was used for polymorphonuclear neutrophils (PMNs) count. Data were analyzed using PROC GLM from SASv9.4. Insemination time, site, sperm dose, and their interactions were considered independent variables and sperm and PMNs numbers dependent variables. Deep horn insemination increased ipsilateral uterine tube sperm number without an increase in the inflammatory reaction compared with the uterine body insemination. The higher the insemination dose, the higher the uterine tubes’ sperm number and inflammatory reaction, with a quicker resolution. In conclusion, the insemination site and dose affected sperm in the uterine tubes, while post-insemination time and dose influenced the inflammatory reaction.
•The higher the number of cryopreserved sperm inseminated, the greater the number of sperm reaching the uterine tubes.•Insemination of 400 × 106 provokes an intense inflammatory reaction, but with a faster resolution compared to 50 × 106 sperm.•More cryopreserved sperm reach the uterine tubes with deep insemination compared with insemination in the uterine body.•Insemination of 50 × 106 cryopreserved semen in the uterine body is not recommended.
Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals ('elite controllers') maintain very low levels of HIV RNA without therapy, ...thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.
Hormonal control of ovulation timing is an effective tool to optimize reproductive management and reduce costs in equine breeding programs. Few studies have evaluated the efficacy of GnRH analog ...histrelin as an ovulation inducer agent. This study aimed to compare the efficacy of human chorionic gonadotrophin (hCG) and histrelin as ovulation inducers in young, adult, and old mares during spring and summer. Reproductive records of 321 estrous cycles of 125 mares, mean age 9.8±0.37 years, range 1.5–24 years, between 360-600 kg body weight, and body condition ≥3 (1/5), were evaluated during spring (151 cycles) and summer (170 cycles). Mares were kept in the field and fed alfalfa hay, balanced concentrate feed and ad-libitum water. The ovaries, uterus, and cervix underwent transrectal examination and ultrasonography daily. When only one dominant follicle of 35 mm and endometrial edema compatible with estrus were reached, ovulation was induced. Each cycle was monitored every two to six hours until ovulation, 24h after induction. Cycles were randomly allotted in two groups; G1 (n=106 cycles): 1500 IU hCG (IV); G2 (n=215 cycles): 250 μg histrelin acetate (IM). A total of 119 cycles were from young (<8 years), 93 from adults (8-15 years), and 109 from old mares (>15 years). Cycles of mares ovulating within 24-48hafter treatment were considered to have responded to the inducer, and those ovulating before 24h and after 48h were excluded from the experiment. Inducer agents, season (spring or summer), and mare age were independent factors, and ovulation between 24-48h was considered the dependent factor. Data were analyzed through Fisher's exact test. The significance level was defined as P<0.05. From the 321 induced cycles, 254 (79.1%) ovulated within 24-48h, 20 (6.2%) before 24h, and 47 (14.6%) after 48h. There were no differences (P=0.2414) in the average response time between G1 (37.2h±3,5) and G2 (39.3h±4,5). The ovulatory response between G1 and G2 did not differ in spring (84.1% versus 90.7%, P=0.2627) and summer (79.2% versus 85.4%, P=0.3534). Independent of the inducer, the season did not influence the ovulation response in the different mare ages (spring P=0.1489; summer P=0.2992). No differences (P=0.896) were found between drugs in young and adult mares. However, old mares had a higher percentage of ovulatory response in spring and summer to histrelin (n=76) than to hCG (n=24) (89.5% versus 45.8%, P<0.0001). In conclusion, histrelin is more effective and accurate in inducing ovulation in old mares (>15 years) than hCG throughout the breeding season.
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