AIDS patient with severe T cell depletion achieved control but not clearance of SARS-CoV-2 infection.

A late presenter AIDS patient with severe T cell depletion presented non-severe COVID-19 symptoms, with prolonged viral shedding. Our case report supports the hypothesis that an effective T cell response may be dispensable for the control of COVID-19 progression to severe forms, while it may be necessary for SARS-CoV-2 clearance.

Long-term Trajectories of C-Reactive Protein Among Men Living With and Without HIV Infection in the Multicenter AIDS Cohort Study.

BACKGROUND: C-reactive protein (CRP) is an inflammatory biomarker associated with all-cause mortality and morbidities such as cardiovascular disease. CRP is increased with HIV infection and thought to increase with age, though trajectories of CRP with aging have not been well characterized. We investigated trajectories of CRP in men from the Multicenter AIDS Cohort Study, according to HIV infection and HIV viral load status. METHODS: CRP measurements from 12 250 serum samples, provided by 2132 men over a span of 30 years, were categorized by HIV status at sample collection: HIV uninfected (HIV-, n = 1717), HIV infected with undetectable RNA (HIV+ suppressed, n = 4075), and detectable HIV RNA (HIV+ detectable, n = 6458). Age-related trajectories of CRP were fit to multivariable linear mixed models; we tested for differences in trajectories by HIV status. RESULTS: CRP increased with age in all sample groups. HIV+ detectable and HIV+ suppressed samples had higher CRP than HIV- samples throughout the observed age range of 20-70 years (p < .05). CRP concentrations at age 45 years were 38% (95% CI: 26%-50%) and 26% (15%-38%) higher in HIV+ detectable and HIV+ suppressed samples, respectively, relative to HIV- samples. HIV+ detectable samples showed more rapid linear increases with age (8% higher/decade, 0.3%-16%) than HIV- samples. CONCLUSIONS: We observed higher concentrations of CRP across 5 decades of age in men living with HIV, and steeper increases with age in men with detectable HIV RNA, relative to HIV- men. These results are consistent with a contribution of inflammation to the higher risk of age-related comorbidities with HIV infection.

CD3+T, CD4+T, CD8+T, and CD4+T/CD8+T Ratio and Quantity of γδT Cells in Peripheral Blood of HIV-Infected/AIDS Patients and Its Clinical Significance.

OBJECTIVE: To investigate the quantity of CD4+T, CD4+T, CD8+T, and γδT cells in peripheral blood of HIV-infected/AIDS patients as well as to explore the possible role of CD4/CD8 ratio and γδT cells in the progression of HIV/AIDS, aimed at providing evidence for the diagnosis and treatment of AIDS. METHODS: The quantity levels of CD3+T cells, CD4+T cells, CD8+T cells, and γδT cells in peripheral blood of 46 HIV-infected/AIDS patients and 30 healthy controls were detected by using flow cytometry. RESULTS: The count of CD3+T, CD4+T, CD8+T, and γδT cells ( x ¯ ± s , A/µl) in the peripheral blood was 1183.64 ± 132.58, 278.39 ± 122.38, 863.13 ± 82.38, and 22.53 ± 1.74 in the experimental group as well as 1456.46 ± 124.37, 788.74 ± 189.67, 569.61 ± 46.49, and 10.96 ± 0.28 in the control group, respectively. The p values of the two groups were <0.005 after the t-test, revealing a statistically significant difference. The proportion of CD3+T, CD4+T, CD8+T, and γδT cells in total lymphocytes in the two groups ( x ¯ ± s , %) was 71.83 ± 5.37, 13.39 ± 2.23, 62.93 ± 5.81, and 3.67 ± 0.87 in the experimental group, respectively. In the control group, the values were expressed as 66.72 ± 5.48, 42.77 ± 3.38, 31.41 ± 3.62, and 1.73 ± 0.36, respectively. After performing the t-test, p values in the two groups were <0.005 except CD3+T, with statistically significant differences. Besides, CD4/CD8 was 0.33 ± 0.11 in the experimental group and 1.48 ± 0.29 in the control group, t = 26.528, p < 0.001, exhibiting a significant statistical difference. CONCLUSION: HIV infection induces the activation and proliferation of CD8+T and γδT cells, contributing to the decrease of CD4+T cells, while CD8+T and γδT cells are involved in the immune response and tissue damage after HIV infection.

Rapid Emergence of T Follicular Helper and Germinal Center B Cells Following Antiretroviral Therapy in Advanced HIV Disease.

Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.

Plasma hemoglobin and the risk of death in HIV/AIDS patients treated with antiretroviral therapy.

BACKGROUND: Previous studies concerning the effect of plasma hemoglobin (HB) and other factors that may modify the risk of death in people living with HIV/AIDS (PLHIV) treated with antiretroviral therapy (ART) are limited. RESULTS: Higher HB was independently linked to a lower death risk in PLHIV, with a decrease of 29% (13%, 43%) per standard deviation (SD) increment after adjusting for CD4, VL and other potential factors [hazard ratio (HR): 0.71, 95% confidence interval (CI): 0.57-0.87, P<0.001]. In addition, the addition of HB to the predictive model containing VL and CD4 significantly improved the C-index, by 0.69% (95% CI: 0.68%-0.71%), and net discrimination, by 0.5% (95% CI: 0.0%-1.6%, P=0.040), when predicting the death risk of PLHIV. CONCLUSIONS: A lower level of HB was an independent risk factor for HIV/AIDS-associated death in PLHIV. HB combined with VL and CD4 may be an appropriate predictive model of the death risk of PLHIV. MATERIALS AND METHODS: A propensity-score matching (PSM) approach was applied to select a total of 750 PLHIV (150 deceased and 600 living) from the AIDS prevention and control information system in the Wenzhou area from 2006 to 2018. Multivariable Cox proportional hazards regression models were formulated to estimate the effect of HB. The predictive performance improvement contributed by HB was evaluated using the C-index and net reclassification improvement.

Survival, CD4 T lymphocyte count recovery and immune reconstitution pattern during the first-line combination antiretroviral therapy in patients with HIV-1 infection in Mongolia.

Mongolia has a low incidence of human immunodeficiency virus (HIV) infection, with 281 cases reported at the end of 2019 and an estimated incidence rate of <0.01 cases per 1000 population. However, no study has analyzed the association between antiretroviral therapy (ART) outcomes and pretreatment characteristics of patients with HIV/acquired immunodeficiency syndrome (AIDS) in Mongolia. This retrospective study aimed to determine the survival, CD4 T cell recovery, and immune reconstitution pattern during ART in HIV patients and to determine baseline patient characteristics associated with ART outcomes. Based on three different World Health Organization (WHO) guidelines, we analyzed the 3-year observation data of 166 patients with HIV/AIDS who received treatment between 2010 and 2017. An increase of >50 cells/µL indicated CD4 T cell count recovery, and a cell count of ≥500 cells/µL in patients with a baseline cell count of <500 cells/µL indicated immune reconstitution. In this study, the 3- and 1-year mortality rates were 5.4% (survival rate: 94.6%) and 3.6%, respectively. A total of 83% of deaths that occurred in the observation time occurred within the first 3 months. The CD4 T cell count recovery rates at 3, 12, and 36 months were 62.7%, 80.7%, and 89.2%, respectively. The CD4 T cell count increased to >500 cells/µL in 95 of 145 (65.5%) patients with a baseline cell count of <500 cells/µL after 36 months of ART. The baseline CD4 T cell count was found to be a sensitive indicator for immune reconstitution. An advanced pretreatment clinical stage of HIV infection (as classified by the WHO classification), a low CD4 T cell count in the peripheral blood, and a high viral load before the initiation of the first-line ART accurately predicted survival, CD4 T cell count recovery, and immune reconstitution in Mongolian patients with HIV/AIDS.

Real-world outcomes of AIDS-related Burkitt lymphoma: a retrospective study of 78 cases over a 10-year period.

We investigated the clinical characteristics and outcomes of acquired immunodeficiency syndrome-related Burkitt lymphoma (AIDS-BL). A single-center retrospective study was performed of 78 cases over a 10-year period. The baseline characteristics of enrolled patients included the following: median age, 46 years; median CD4+ T lymphocyte count, 156 cells/µL; advanced stage, 74.3%; > 1 extranodal site, 55.1%; international prognostic index (IPI) > 1, 85.9%; and elevated serum lactate dehydrogenase, 82.1%. The 1-year and 2-year overall survival (OS) rates were 52.2 ± 5.9% and 42.7 ± 6.2%, respectively. A prognostic analysis of 65 patients who had undergone chemotherapy showed that B symptoms (with vs. without fever, night sweat or weight loss), number of extranodal sites (0, 1 vs. > 1), level of serum albumin (≥ 35 g/L vs. < 35 g/L), hemoglobin (≥ 110 g/L vs. < 110 g/L), and IPI score (≤ 2 vs. > 1) were all associated with OS. However, only B symptoms (HR = 4.036, 95% CI 1.821-8.948, p = 0.001), serum albumin level < 35 g/L (HR = 2.131, 95% CI 1.013-4.483, p = 0.046), and chemotherapy without rituximab (HR = 2.286, 95% CI 1.108-4.714, p = 0.025) were independent predictors of OS after multivariate adjustment. Patients with AIDS-BL were likely to present with high-risk features, and their clinical outcomes were relatively poor, especially those with B symptoms and lower serum albumin levels.

A comparison of medication adherence and viral suppression in antiretroviral treatment-naïve patients with HIV/AIDS depending on the drug formulary.

Antiretroviral treatment (ART) adherence is highlighted in management of patients living with human immunodeficiency virus. In South Korea, ART medication research has rarely been conducted due to the low economic burden associated with government-funded treatment. This cross-sectional study aimed to compare the pill burden impact between ART regimen compliance and HIV-RNA viral load suppression. Data were collected from 2008 to 2016 at a general hospital in South Korea. A total of 210 HIV/AIDS treatment-naïve patients were grouped as follows: single-tablet regimen (STR, one tablet/day), mild pill burden (two-four tablets/day), and heavy pill burden (≥ five tablets/day). Patients were analyzed according to gender, age at index date, medical insurance type, comorbidities, depression, HIV/AIDS disease burden as indicated by HIV-RNA viral load and CD4, and laboratory variables. In a multivariate logistic regression model, the STR group demonstrated adherence 5.10 times more often than the heavy pill burden group. Females and patients with an initial viral load of 500,000 or more were 0.090- and 0.040-fold less adherent to the ART regimen. Among these patients, 95% or more of the MPR group were 7.38 times more likely to have a lower limit of detection (LLOD) of viral load suppression. The highest initial viral load group was 0.090-fold less likely to have an LLOD than the reference group. These results suggest that a single-tablet regimen could improve medication adherence and the clinical virologic outcome. Therefore, general population research on ART adherence and polypharmacy is needed.

Human aflatoxin exposure in Uganda: Estimates from a subset of the 2011 Uganda AIDS indicator survey (UAIS).

Aflatoxins are carcinogenic mycotoxins that contaminate a variety of crops worldwide. Acute exposure can cause liver failure, and chronic exposure can lead to stunting in children and liver cancer in adults. We estimated aflatoxin exposure across Uganda by measuring a serum biomarker of aflatoxin exposure in a subsample from the 2011 Uganda AIDS Indicator Survey, a nationally representative survey of HIV prevalence, and examined its association with geographic, demographic, and socioeconomic variables. We analysed a subsample of 985 serum specimens selected among HIV-negative participants from 10 survey-defined geographic regions for serum aflatoxin B1-lysine (AFB1-lys) by use of isotope dilution LC-MS/MS and calculated results normalised to serum albumin. We used statistical techniques for censored data to estimate geometric means (GMs), standard deviations, and percentiles. We detected serum AFB1-lys in 71.7% of specimens (LOD = 0.5 pg/mg albumin). Unadjusted GM AFB1-lys (pg/mg albumin) was 1.33 (95% CI: 1.21-1.47). Serum AFB1-lys was higher in males (GM: 1.57; 95% CI: 1.38-1.80) vs. females (GM: 1.12; 95% CI: 0.97-1.30) (P = .0019), and higher in persons residing in urban settings (GM: 2.83; 95% CI: 2.37-3.37) vs. rural (GM: 1.10; 95% CI: 0.99-1.23) (P < .0001). When we used a multivariable censored regression model to assess confounding and interactions among variables we found that survey region, gender, age, occupation, distance to marketplace, and number of meals per day were statistically significant predictors of aflatoxin exposure. While not nationally representative, our findings provide an improved understanding of the widespread burden of aflatoxin exposure throughout Uganda and identify key geographic, demographic, and socioeconomic factors that may modulate aflatoxin exposure risk.

DNA methylation changes in metabolic and immune-regulatory pathways in blood and lymph node CD4 + T cells in response to SIV infections.

The molecular mechanisms underlying HIV-induced inflammation, which persists even during effective long-term treatment, remain incompletely defined. Here, we studied pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections in macaques and African green monkeys, respectively. We longitudinally analyzed genome-wide DNA methylation changes in CD4 + T cells from lymph node and blood, using arrays. DNA methylation changes after SIV infection were more pronounced in lymph nodes than blood and already detected in primary infection. Differentially methylated genes in pathogenic SIV infection were enriched for Th1-signaling (e.g., RUNX3, STAT4, NFKB1) and metabolic pathways (e.g., PRKCZ). In contrast, nonpathogenic SIVagm infection induced DNA methylation in genes coding for regulatory proteins such as LAG-3, arginase-2, interleukin-21 and interleukin-31. Between 15 and 18% of genes with DNA methylation changes were differentially expressed in CD4 + T cells in vivo. Selected identified sites were validated using bisulfite pyrosequencing in an independent cohort of uninfected, viremic and SIV controller macaques. Altered DNA methylation was confirmed in blood and lymph node CD4 + T cells in viremic macaques but was notably absent from SIV controller macaques. Our study identified key genes differentially methylated already in primary infection and in tissues that could contribute to the persisting metabolic disorders and inflammation in HIV-infected individuals despite effective treatment.

Plasma Levels of a Cleaved Form of Galectin-9 Are the Most Sensitive Biomarkers of Acquired Immune Deficiency Syndrome and Tuberculosis Coinfection.

Acquired immunodeficiency syndrome (AIDS) complicated with tuberculosis (TB) is a global public issue. Due to the paucity of bacteria in AIDS/TB, blood-based biomarkers that reflect disease severity are desired. Plasma levels of matricellular proteins, such as osteopontin (OPN) and galectin-9 (Gal-9), are known to be elevated in AIDS and TB. Therefore, full-length (FL)-Gal9 and FL-OPN, and their truncated forms (Tr-Gal9, Ud-OPN), and 38 cytokines/chemokines were measured in the plasma of 24 AIDS (other than TB), 49 TB, and 33 AIDS/TB patients. Receiver-operating characteristic analysis was used to screen molecules that could distinguish either between disease and normal group, among each disease group, or between deceased patients and survivors. Selected molecules were further analyzed for significant differences. Tr-Gal9 had the highest ability to differentiate TB from AIDS or AIDS/TB, while Ud-OPN distinguished multidrug resistance (MDR)-TB from non-MDR TB, and extra-pulmonary TB from pulmonary TB. Molecules significantly elevated in deceased patients included; FL-Gal9, Tr-Gal9, interleukin (IL)-1 receptor antagonist, IL-17A and transforming growth factor-α in AIDS; IL-6, granulocyte colony-stimulating factor and monocyte chemotactic protein-1 in TB; and macrophage inflammatory protein-1ß in AIDS/TB. From the sensitivity, specificity, and significant elevation, Tr-Gal9 is the best biomarker of inflammation and severity in AIDS and AIDS/TB.

Etiologia da anemia em pessoas infectadas com HIV / Anemia etiology in HIV-infected people

O HIV é o causador da AIDS, doença que representa um dos grandes problemas de saúde pública em todo o mundo. Apesar de avanços na terapia antirretroviral no sentido de aumentar a expectativa de vida dos indivíduos infectados, as alterações hematológicas, como a anemia, acompanham o curso clínico da doença. Essa condição, normalmente multifatorial, pode estar presente em qualquer fase da doença e afeta diretamente o prognóstico e a qualidade de vida do indivíduo infectado. Este artigo apresenta informações do surgimento do processo anêmico com base nas principais causas encontradas na literatura.

The human immunodeficiency virus is the cause of the acquired immunodeficiency syndrome, a disease that represents one of the major public health problems worldwide. In spite of advances in antiretroviral therapy that increase patients' life expectancy, hematological changes, such as anemia, follow the clinical course of the disease. This commonly multifactorial condition can be found in any phase of the disease and directly affects the prognosis and quality of life of patients. This article presents information on the emergence of the anemic process based on the main causes found in the literature.

A Markov model for the effects of virological failure on HIV/AIDS progression in tuberculosis co-infected patients receiving antiretroviral therapy in a rural clinic in northern South Africa.

BACKGROUND: The goal of antiretroviral therapy (ART) is to suppress viral replication to undetectable levels. These low viral load (VL) levels may not be attained in some patients, a situation representing potential virological failure during the course of treatment. OBJECTIVES: To present the results of a Markov model exploring how virological failure and active tuberculosis (TB) affect the progression of HIV in patients on ART. METHODS: A continuous-time non-homogeneous Markov model was used to model the progression of HIV/AIDS in patients on combination ART (cART). We define seven states in our model. The first five states are based on VL levels and the other two are absorbing states: death and withdrawal from the study. The effects of TB co-infection, baseline VL, lactic acidosis and treatment failure on transition intensities were assessed. RESULTS: The model shows that VL-based transition intensities do not follow a constant rate; rather, there are two different trends in HIV/AIDS progression. The first trend is an increase in the prevalence of state 1 (undetectable VL levels) in the first 0.5 years of treatment. The second trend follows thereafter and shows a slow decrease. Within the first 0.5 years of therapeutic intervention, the undetectable VL state is therefore attainable from any VL state. However, when virological failure occurs, there is an increased risk of death. Developing active TB while on cART increases the risk of viral rebound from undetectable levels to VLs between 50 and 10 000 copies/mL by ~1.03-fold. From a VL between 10 000 and 100 000 copies/mL, developing TB while on cART increases the rate of viral rebound by ~2.5-fold. However, if TB is detected and treated at enrolment, rates of viral rebound from undetectable levels are reduced. CONCLUSIONS: The model confirms that virological failure, coupled with developing active TB while on cART, increases mortality rates irrespective of patient CD4+ count status. It also suggests that while TB at the time of cART initiation does not increase the risk of viral rebound, development of active TB after cART initiation does increase this risk. These findings highlight the importance of strengthening VL monitoring, which should be performed every 2 months, especially in patients with TB, and addressing unsuppressed VLs appropriately if they are detected.

Vascular function and cardiovascular risk in a HIV infected and HIV free cohort of African ancestry: baseline profile, rationale and methods of the longitudinal EndoAfrica-NWU study.

BACKGROUND: People living with the Human Immunodeficiency Virus (PLHIV) have an increased susceptibility to develop non-communicable diseases such as cardiovascular disease (CVD). Infection with HIV contributes to the development of CVD independent of traditional risk factors, with endothelial dysfunction being the central physiological mechanism. While HIV-related mortality is declining due to antiretroviral treatment (ART), the number of deaths due to CVD is rising in South Africa - the country with the highest number of PLHIV and the world's largest ART programme. The EndoAfrica study was developed to determine whether HIV infection and ART are associated with cardiovascular risk markers and changes in vascular structure and function over 18 months in adults from different provinces of South Africa. This paper describes the rationale, methodology and baseline cohort profile of the EndoAfrica study conducted in the North West Province, South Africa. METHODS: In this case-control study, conducted between August 2017 and June 2018, 382 volunteers of African descent (276 women; 106 men), comprising of 278 HIV infected and 104 HIV free individuals were included. We measured health behaviours, a detailed cardiovascular profile, and performed biomarker analyses. We compared baseline characteristics, blood pressure, vascular function and biochemical markers between those infected and HIV free. RESULTS: At baseline, the HIV infected participants were older (43 vs 39 years), less were employed (21% vs 40%), less had a tertiary education (7% vs 16%) and their body mass index was lower (26 vs 29 kg/m2) than that of the HIV free participants. While the cardiovascular profile, flow-mediated dilation and pulse wave velocity did not differ, glycated haemoglobin was lower (p = 0.017) and total cholesterol, high density lipoprotein cholesterol, triglycerides, gamma-glutamyltransferase and tobacco use were higher (all p < 0.047) in PLHIV. CONCLUSION: Despite PLHIV being older, preliminary cross-sectional analysis suggests that PLHIV being treated with ART do not have poorer endothelial or vascular function compared to the HIV free participants. More detailed analyses on the baseline and follow-up data will provide further clarity regarding the cardiovascular profile of South Africans living with HIV.

Prevalence and determinants of virological failure, genetic diversity and drug resistance among people living with HIV in a minority area in China: a population-based study.

BACKGROUND: Liangshan Yi Autonomous Prefecture is one of the areas that most severely affected by human immunodeficiency virus (HIV) in China, and virological failure on antiretroviral therapy (ART) is serious in this area. Analyses of prevalence and determinants of ART failure, the genetic diversity and drug resistance among people living with HIV (PLWH) helps improve HIV treatment efficiency and prevent HIV transmission. METHODS: A total of 5157 PLWH were recruited from 2016 to 2017. The venous blood samples were subjected to RT-PCR, followed by sequencing of the HIV-1 pol gene, targeting the protease and reverse transcriptase fragments. HIV-1 diversity was analyzed using the DNAStar software and drug resistance mutations were analyzed using the Stanford University HIV Drug Resistance Database. RESULTS: A total of 2156 (41.81%) PLWH showed virological failure on ART. Males (ORm = 1.25), heterosexual behaviors and drug injection (ORm = 1.44) and mother to child transmission routes (ORm = 1.58), the clinical stage of AIDS (ORm = 1.35), having used illicit drugs and shared the needles (1-4 times: ORm = 1.34; more than 5 times: ORm = 1.52), having ever replaced ART regimen (ORm = 1.48) increased the risk of virological failure among PLWH, while higher education lever (ORm = 0.77) and ≥ 12 months on ART (12 ~ 36 months: ORm = 0.72; ≥36 months: ORm = 0.66) was associated with lower likelihood of virological failure. The data revealed that CRF07_BC (1508, 95.62%) were the most common strains, and the drug-resistant rate was 32.10% among PLWH with virological failure in this area. The high frequencies of drug resistance were found in EFV and NVP of NNRTIs, ABC, FTC and 3TC of NRTIs, and TPV/r in PIs. The most common mutations in NNRTIs, NRTIs and PIs were K103N/KN (64.69%), M184V/MV/I (36.29%) and Q58E/QE (4.93%), respectively. CONCLUSION: We concluded that surveillance of virological failure, HIV-1 subtypes, and drug resistance to understand HIV-1 epidemiology and guide modification of ART guidelines, and target prevention and control strategies should be formatted to reduce the virological failure and drug resistance to promote viral suppression and prevent HIV-1 transmission.

Immunotherapy with DNA vaccine and live attenuated rubella/SIV gag vectors plus early ART can prevent SIVmac251 viral rebound in acutely infected rhesus macaques.

Anti-retroviral therapy (ART) has been highly successful in controlling HIV replication, reducing viral burden, and preventing both progression to AIDS and viral transmission. Yet, ART alone cannot cure the infection. Even after years of successful therapy, ART withdrawal leads inevitably to viral rebound within a few weeks or months. Our hypothesis: effective therapy must control both the replicating virus pool and the reactivatable latent viral reservoir. To do this, we have combined ART and immunotherapy to attack both viral pools simultaneously. The vaccine regimen consisted of DNA vaccine expressing SIV Gag, followed by a boost with live attenuated rubella/gag vectors. The vectors grow well in rhesus macaques, and they are potent immunogens when used in a prime and boost strategy. We infected rhesus macaques by high dose mucosal challenge with virulent SIVmac251 and waited three days to allow viral dissemination and establishment of a reactivatable viral reservoir before starting ART. While on ART, the control group received control DNA and empty rubella vaccine, while the immunotherapy group received DNA/gag prime, followed by boosts with rubella vectors expressing SIV gag over 27 weeks. Both groups had a vaccine "take" to rubella, and the vaccine group developed antibodies and T cells specific for Gag. Five weeks after the last immunization, we stopped ART and monitored virus rebound. All four control animals eventually had a viral rebound, and two were euthanized for AIDS. One control macaque did not rebound until 2 years after ART release. In contrast, there was only one viral rebound in the vaccine group. Three out of four vaccinees had no viral rebound, even after CD8 depletion, and they remain in drug-free viral remission more than 2.5 years later. The strategy of early ART combined with immunotherapy can produce a sustained SIV remission in macaques and may be relevant for immunotherapy of HIV in humans.

The stage-specific impairment of granulopoiesis in people living with HIV/AIDS (PLWHA) with neutropenia.

Neutropenia and impaired functions were common manifestation in antiretroviral therapy (ART) in both naïve and experienced PLWHA. Granulopoiesis can be divided into two phases: lineage determination and committed granulopoiesis. However, stage-specific impairment of granulopoiesis in PLWHA with neutropenia remains unclear. A total of 48 ART-naïve and 49 ART-experienced PLWHA from 2016 to 2018 were recruited and divided into non-, mild-, and moderate-to-severe-neutropenia groups according to their neutrophil counts. The bone marrow aspirates and peripheral blood were collected and analyzed by multicolor flow cytometry for granulocyte subsets, hematopoietic stem/progenitor cells (HSPC), apoptosis, and emigration and retention of different subsets. Compared with healthy donors, the percentages of circulating segmented neutrophils were significantly decreased along with an increase of immature neutrophils in both groups. ART-naïve patients with moderate to severe neutropenia exhibited decreased proportion and accelerated apoptosis of relative mature segmented neutrophils. In contrast, ART-experienced patients with neutropenia displayed decreased proportion of granulocyte macrophage progenitors, indicating a defect at a stage of lineage determination. Meanwhile, ART-experienced patients with neutropenia also the expression of CXCR4 segmented neutrophils, suggesting an increased retention of segmented neutrophils inn the bone marrow. ART-naïve patients with neutropenia is caused by increased apoptosis of relatively differentiated neutrophils at committed granulopoiesis, whereas impaired lineage determination and enhanced retention of segmented neutrophils contribute to in ART-experienced patients.