CD4+ T cells re-wire granuloma cellularity and regulatory networks to promote immunomodulation following Mtb reinfection.

Immunological priming-in the context of either prior infection or vaccination-elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrated that prior Mtb infection elicited a long-lasting protective response against subsequent Mtb exposure and was CD4+ T cell dependent. By analyzing data from primary infection, reinfection, and reinfection-CD4+ T cell-depleted granulomas, we found that the presence of CD4+ T cells during reinfection resulted in a less inflammatory lung milieu characterized by reprogrammed CD8+ T cells, reduced neutrophilia, and blunted type 1 immune signaling among myeloid cells. These results open avenues for developing vaccines and therapeutics that not only target lymphocytes but also modulate innate immune cells to limit tuberculosis (TB) disease.

Idiopathic CD4+ T lymphocytopenia: A case report.

Idiopathic CD4+ T lymphocytopenia (ICL) is a very rare immunodeficiency syndrome with an unexplained depletion of CD4+ T lymphocytes and no evidence of Human Immunodeficiency Virus (HIV) infection. Here we report a 29-year-old male patient who had severe ulcerative colitis with low level CD4+ count of 254 cells/mm3, and had no evidence of HIV or Human T cell Lymphotrophic virus type I or II infections. He had recurrent Candidiasis infection and his CD4 count was just 53 cells/mm3 after 3 months. The cause for the decline of CD4 T lymphocytes was unknown.

Long-term efficient control of SIV infection in macaques is associated with an intact intestinal barrier.

Hallmarks of SIV infection are early depletion of gut CD4 T cells and diminished intestinal integrity. Comprehensive studies on colon biopsies of SIV-infected macaques efficiently controlling infection revealed that in contrast to viremic and failing controllers, elite controllers show preserved CD4 T cells, and low viral load, apoptosis, and inflammation.

Immuno-virological and clinical impacts of treating cancer in patients living with HIV.

BACKGROUND: Patients living with HIV (PLHIV) are increasingly being affected by cancer. However, data evaluating the long-term impact of cancer treatment on HIV course are sparse. METHODS: To determine whether anticancer treatments detrimentally impact HIV course, we conducted a retrospective cohort study in seven hospitals in France. Adult PLHIV treated for haematological or solid malignancies were included and compared (1:1) with suitably matched (cancer-free) controls. The primary outcome was the risk of a ≥ 25% reduction in the absolute CD4+ count during follow-up. The risks for virological failure (i.e. a confirmed plasma viral load >50 copies/mL), incidental AIDS-related illnesses and death over time were also assessed. Multivariate Cox proportional-hazards regression analyses were used to identify the outcome predictors. RESULTS: One-hundred-and-ten patients with cancer and 110 controls were followed for a median of 4.4 years. In a Cox model, the CD4+ depletion was strongly predicted by external radiotherapy (ERT) exposure (HR = 5.1, 95% CI, 3.0-8.6, P < 0.0001) but not by chemotherapy. For patients exposed to ERT, the magnitude of the CD4+ depletion peaked 6 months after their cancer diagnosis (mean CD4+ drop at this time =  -283 ± 370 cells/mm(3)). Overall, the cancer patients were also more likely to experience virological failure than the controls (HR = 1.7, 95% CI, 1.1-2.7, P = 0.03). Finally, the incidence of AIDS-related illnesses was similar for both groups. CONCLUSIONS: In PLHIV, cancer treatment increased the risk for prolonged CD4+ depletion and virological failure but had no impact on AIDS-related events when appropriate prophylaxes were implemented.

A single amino-acid change in a highly conserved motif of gp41 elicits HIV-1 neutralization and protects against CD4 depletion.

BACKGROUND: The induction of neutralizing antibodies against conserved regions of the human immunodeficiency virus type 1 (HIV-1) envelope protein is a major goal of vaccine strategies. We previously identified 3S, a critical conserved motif of gp41 that induces the NKp44L ligand of an activating NK receptor. In vivo, anti-3S antibodies protect against the natural killer (NK) cell-mediated CD4 depletion that occurs without efficient viral neutralization. METHODS: Specific substitutions within the 3S peptide motif were prepared by directed mutagenesis. Virus production was monitored by measuring the p24 production. Neutralization assays were performed with immune-purified antibodies from immunized mice and a cohort of HIV-infected patients. Expression of NKp44L on CD4(+) T cells and degranulation assay on activating NK cells were both performed by flow cytometry. RESULTS: Here, we show that specific substitutions in the 3S motif reduce viral infection without affecting gp41 production, while decreasing both its capacity to induce NKp44L expression on CD4(+) T cells and its sensitivity to autologous NK cells. Generation of antibodies in mice against the W614 specific position in the 3S motif elicited a capacity to neutralize cross-clade viruses, notable in its magnitude, breadth, and durability. Antibodies against this 3S variant were also detected in sera from some HIV-1-infected patients, demonstrating both neutralization activity and protection against CD4 depletion. CONCLUSIONS: These findings suggest that a specific substitution in a 3S-based immunogen might allow the generation of specific antibodies, providing a foundation for a rational vaccine that combine a capacity to neutralize HIV-1 and to protect CD4(+) T cells.

Duration of delayed diagnosis in HIV/AIDS patients in Iran: a CD4 depletion model analysis.

Objective: Delayed diagnosis of HIV can lead to an inappropriate response to antiretroviral therapy (ART), rapid progression of the disease, and death. It can also carry harmful effects on public health due to the increment of transmission. This study aimed to estimate the duration of delayed diagnosis (DDD) in HIV patients in Iran. Methods: This hybrid cross-sectional cohort study was conducted on the national HIV surveillance system database (HSSD). Linear mixed effect models with random intercept, random slope, and both were used to estimate the parameters required for the CD4 depletion model to determine the best-fitted model for DDD, stratified by the route of transmission, gender, and age group. Results: The DDD was estimated in 11,373 patients including 4,762 (41.87%) injection drug users (IDUs), 512 (4.5%) men who had sexual contact with men (MSM), 3,762 (33.08%) patients with heterosexual contacts, and 2,337 (20.55%) patients who were infected through other routes of HIV transmission. The total mean DDD was 8.41 ± 5.97 years. The mean DDD was 7.24 ± 0.08 and 9.43 ± 6.83 years in male and female IDUs, respectively. In the heterosexual contact group, DDD was obtained as 8.60 ± 6.43 years in male patients and 9.49 ± 7.17 years in female patients. It was also estimated as 9.37 ± 7.30 years in the MSM group. Furthermore, patients infected through other transmission routes were found with a DDD of 7.90 ± 6.74 years for male patients and a DDD of 7.87 ± 5.87 years for female patients. Conclusion: A simple CD4 depletion model analysis is represented, which incorporates a pre-estimation step to determine the best-fitted linear mixed model for calculating the parameters required for the CD4 depletion model. Considering such a noticeably high HIV diagnostic delay, especially in older adults, MSM, and heterosexual contact groups, regular periodic screening is required to reduce the DDD.

Assessing linear CD4 decline quantifying diagnosis delay after HIV seroconversion: assessing the linearity assumption of CD4 decline.

PURPOSE: To estimate time from seroconversion to diagnosis, researchers have modeled time based on CD4 decline, assuming the square root of the CD4 count decreases linearly over time before antiretroviral treatment (ART) initiation. If true, utilizing CD4 counts reported anytime in the pre-ART period would result in estimates of diagnosis delay that are not appreciably different. METHODS: We applied CD4 depletion model parameters from seroconverter cohorts to New York City residents diagnosed from 2006 to 2015, having two or more pre-ART CD4 counts. RESULTS: Median diagnosis delays based on first or second pre-ART CD4 counts were similar (n = 12,849; 2.8 years, interquartile range [IQR]: 0-7.7, and 2.8 years, IQR: 0-7.6, respectively; P = .09, Wilcoxon signed-rank test). Among people whose second pre-ART CD4 count was measured more than 6 months after diagnosis (n = 2761), the average diagnosis delay based on first pre-ART CD4 count was shorter (1.5 years, IQR: 0-5.4) than the second pre-ART CD4 count (1.7 years, IQR: 0-6.0) but not significantly (P = .12). CONCLUSIONS: Results are consistent with the linearity assumption of the CD4 depletion model. To estimate population-level diagnosis delay, researchers may use pre-ART CD4 counts reported more than 6 months post-diagnosis.