Joel N. Blankson

Elucidating the elite: mechanisms of control in HIV-1 infection

In patients with progressive disease, untreated HIV-1 infection is characterized by high viral loads and decreasing CD4(+)T cell counts which lead to opportunistic infection and other AIDS-defining illness. A rare subset of patients termed elite controllers (ECs) maintain control over viremia and often retain normal CD4(+)T cell levels without treatment with antiretroviral drugs. For the most part these patients are infected with replication-competent, fit virus. Factors such as strong, polyfunctional cytotoxic T lymphocyte (CTL) responses and retention of T cell proliferative ability appear to be important in control of HIV-1. Defining what enables ECs to control viral replication will aid in the development of effective vaccine and treatment regimens. This review will discuss differences between ECs and progressors while emphasizing recent findings on the immunological response of ECs to HIV-1.

Evolution of HIV-1 in an HLA-B*57-Positive Patient during Virologic Escape

Elite suppressors maintain normal CD4(+) T cell counts and viral loads of <50 copies of human immunodeficiency virus type 1 (HIV-1) RNA per milliliter of plasma without antiviral therapy. We report here a case of virologic escape in a human leukocyte antigen (HLA)-B*57-positive patient shortly after seroconversion. This escape was associated with the development of mutations in 2 HLA-B*57-restricted CD8(+) T cell Gag epitopes, reversion of the drug-resistance mutation M184V, and reversion of a novel polymorphism in Vpu. The present study suggests that control of viral replication in elite suppressors may be due to HIV-1-specific CD8(+) T cells and, in some cases, mutations that have subtle effects on viral fitness.

Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons With Medically Controlled HIV Infection

BACKGROUNDnElite controllers spontaneously suppress human immunodeficiency virus (HIV) viremia but also demonstrate chronic inflammation that may increase risk of comorbid conditions. We compared hospitalization rates and causes among elite controllers to those of immunologically intact persons with medically controlled HIV.nnnMETHODSnFor adults in care at 11 sites from 2005 to 2011, person-years with CD4 T-cell counts ≥350 cells/mm(2) were categorized as medical control, elite control, low viremia, or high viremia. All-cause and diagnostic category-specific hospitalization rates were compared between groups using negative binomial regression.nnnRESULTSnWe identified 149 elite controllers (0.4%) among 34 354 persons in care. Unadjusted hospitalization rates among the medical control, elite control, low-viremia, and high-viremia groups were 10.5, 23.3, 12.6, and 16.9 per 100 person-years, respectively. After adjustment for demographic and clinical factors, elite control was associated with higher rates of all-cause (adjusted incidence rate ratio, 1.77 [95% confidence interval, 1.21-2.60]), cardiovascular (3.19 [1.50-6.79]) and psychiatric (3.98 [1.54-10.28]) hospitalization than was medical control. Non-AIDS-defining infections were the most common reason for admission overall (24.1% of hospitalizations) but were rare among elite controllers (2.7%), in whom cardiovascular hospitalizations were most common (31.1%).nnnCONCLUSIONSnElite controllers are hospitalized more frequently than persons with medically controlled HIV and cardiovascular hospitalizations are an important contributor.

Sprouty-2 regulates HIV-specific T cell polyfunctionality

The ability of individual T cells to perform multiple effector functions is crucial for protective immunity against viruses and cancer. This polyfunctionality is frequently lost during chronic infections; however, the molecular mechanisms driving T cell polyfunctionality are poorly understood. We found that human T cells stimulated by a high concentration of antigen lacked polyfunctionality and expressed a transcription profile similar to that of exhausted T cells. One specific pathway implicated by the transcription profile in control of T cell polyfunctionality was the MAPK/ERK pathway. This pathway was altered in response to different antigen concentrations, and polyfunctionality correlated with upregulation of phosphorylated ERK. T cells that were stimulated with a high concentration of antigen upregulated sprouty-2 (SPRY2), a negative regulator of the MAPK/ERK pathway. The clinical relevance of SPRY2 was confirmed by examining SPRY2 expression in HIV-specific T cells, where high levels of SPRY2 were seen in HIV-specific T cells and inhibition of SPRY2 expression enhanced the HIV-specific polyfunctional response independently of the PD-1 pathway. Our findings indicate that increased SPRY2 expression during chronic viral infection reduces T cell polyfunctionality and identify SPRY2 as a potential target for immunotherapy.

Failure to Identify HIV-Infected Individuals in a Clinical Trial Using a Single HIV Rapid Test for Screening

Abstract Background: In the HIV Prevention Trials Network (HPTN) 061 study, 8 (2.3%) of 348 HIV-infected participants identified as HIV uninfected at study enrollment using a single HIV rapid test for screening were found to be HIV infected after additional testing. Objectives: To evaluate the performance of different HIV assays for detection of HIV infection in HPTN 061 participants with missed infection and individuals with viral suppression. Methods: Plasma samples from 8 HPTN 061 participants, 17 elite controllers, and 101 individuals on antiretroviral treatment (ART) were tested for HIV with 3 rapid tests, 2 laboratory-based immunoassays, and a Western blot assay. The HPTN 061 samples were also tested with 2 HIV RNA assays and an antiretroviral drug assay. Results: Of the 8 HPTN 061 participants with missed infection, 1 was an elite controller, 1 was taking ART, 2 were missed because of testing or clerical errors, 1 had recent HIV infection (identified using a multi-assay algorithm), and 3 had acute HIV infection. Two (1.7%) of 118 individuals with viral suppression (both taking ART) had at least 1 false-negative test. Conclusions: In clinical trials, HIV infections can be missed for a variety of reasons. Using more than one assay to screen for HIV infection may reduce the number of missed infections.

HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells

Type I IFN production is essential for innate control of acute viral infection; however, prolonged high-level IFN production is associated with chronic immune activation in HIV-infected individuals. Although plasmacytoid DCs (pDCs) are a primary source of IFN, the mechanisms that regulate IFN levels following the acute phase are unknown. We hypothesized that HIV-specific Ab responses regulate late IFN production. We evaluated the mechanism through which HIV-activated pDCs produce IFN as well as how both monoclonal HIV-specific Abs and Abs produced in natural HIV infection modulated normal pDC sensing of HIV. We found that HIV-induced IFN production required TLR7 signaling, receptor-mediated entry, fusion, and viral uncoating, but not endocytosis or HIV life cycle stages after uncoating. Abs directed against the HIV envelope that do not interfere with CD4 binding markedly enhanced the IFN response, irrespective of their ability to neutralize CD4+ T cell infection. Ab-mediated enhancement of IFN production required Fc &ggr; receptor engagement, bypassed fusion, and initiated signaling through both TLR7 and TLR9, which was not utilized in the absence of Ab. Polyclonal Abs isolated from HIV-infected subjects also enhanced pDC production of IFN in response to HIV. Our data provide an explanation for high levels of IFN production and immune activation in chronic HIV infection.

HIV-1 and hematopoietic stem cell transplantation.

Acquired immune deficiency syndrome (AIDS) was in part recognized because of the unusual occurrence of aggressive B cell lymphomas and opportunistic infections in the same patients. Because the lymphomas typically presented in advanced stage, some of the earliest attempts at treatment were very aggressive. It soon emerged that the complications of chemotherapy that might be anticipated in the general population were much more likely to occur in patients with AIDS and lymphoma. Standard lymphoma regimens were replaced by reduced-dose lymphoma regimens and high-dose strategies involving stem cell rescue were deemed inappropriate. However, with advances in supportive care including routine use of pneumocystis prophylaxis, leukocyte growth factors, and effective antiretroviral therapy (ART), standard-dose lymphoma therapies became standard for AIDS lymphoma patients and stage for stage, outcomes were comparable or even better than in the general population. High-dose therapy with autologous stem cell rescue was pursued at several centers and in small cooperative group trials, and the results were similar to what was achieved with high-dose therapy in the general population. Specifically, mortality among HIV-1-infected patients with lymphoma who went to transplant was largely a function of relapsed or progressive lymphoma or occasionally organ toxicity (veno-occlusive disease) rather than opportunistic infection. Many patients achieved sustained remission and were likely cured. Small numbers of allogeneic transplants followed, and in the era of effective ART yielded encouraging results. Outcomes for a very small number of patients appear similar to what might be expected in the general population. Among the recipients of allotransplant was a patient in Berlin with acute myelogenous leukemia (AML) who received a graft from a donor who was homozygous for a polymorphism that confers resistance to HIV-1 infection; ART was discontinued and 3.5 years later it appears that the patient was cured of AML and of HIV-1. Hence, this special symposium is presented with a focus on aspects of HIV-1 biology, innate and adaptive resistance, genetically engineered resistance, practical aspects of the autologous and allogeneic hematopoietic stem cell transplant, and consideration of the possibility that the use of partially matched unrelated donors might increase the opportunity to cure malignancy as well as HIV-1 infection.

Highly Attenuated Infection With a Vpr-Deleted Molecular Clone of Human Immunodeficiency Virus-1

A 48-year-old woman was infected with a vpr-defective human immunodeficiency virus (HIV)-1 molecular clone. Seroconversion was markedly delayed, and without treatment she had durably suppressed viremia and normal T-cell levels. Neutralizing antibody and CD8+ T-cell immune responses against HIV-1 were unremarkable. Viral sequences confirmed the source but evolved defective nef, suggesting an unknown mechanistic link to vpr. There were subtle qualitative defects in T and B cells. To our knowledge, this is the only case of human infection with a characterized defective HIV-1 molecular clone, which furthermore recapitulated live-attenuated vaccination in macaque models of HIV-1 vaccine research.

Candida Esophagitis in a Human Immunodeficiency Virus-1-Positive Elite Controller With Hepatitis C Virus Cirrhosis

We describe a case of Candida esophagitis in a human immunodeficiency virus elite controller with a preserved CD4 count, a population in which opportunistic infections are almost never seen. The patient has hepatitis C virus coinfection and compensated cirrhosis, suggesting a possible multifactorial etiology of immune dysregulation.