Search

Rapid and synchronized responses of innate immune cells are an integral part of managing viral spread in acute virus infections. In human immunodeficiency virus type 1 (HIV-1) infection, increased immune control has been associated with the expression of certain natural killer (NK) cell receptors. Further, immune activation of monocytes/macrophages and the presence of specific cytokines was linked to low levels of HIV-1 replication. In addition to the intrinsic antiviral capabilities of NK cells and monocytes/macrophages, interaction between these cell types has been shown to substantially enhance NK cell function in the context of viral infections. This review discusses the involvement of NK cells and monocytes/macrophages in the effective control of HIV-1 and highlights aspects of innate immune crosstalk in viral infections that may be of relevance to HIV-1 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mensching and Hoelzemer.)

In most HIV-infected persons, the natural history of untreated infection is one of sustained viremia, progressive CD4 T cell depletion with resultant morbidity and mortality. The advent of effective combination antiretroviral therapy (ART) that controls HIV replication has altered this landscape dramatically. Yet a rare population of HIV-infected persons-elite controllers (EC)-can control HIV replication such that plasma levels of virus are "undetectable" without ART. The EC phenotype is heterogeneous, with some subjects durably controlling the virus-persistent elite controllers-and some eventually losing viral control-transient elite controllers. Overall, EC tend to have robust HIV-specific T cell responses and in some cases, mainly in transient elite controllers, elevated activation and inflammation indices that diminish with ART suggesting that endogenous defenses against this persistent pathogen come at the cost of heightened activation/inflammation. A limited data set suggests that cardiovascular disease risk as well as the occur-rence of other morbid events may be greater in the overall EC population than in treated HIV infection. ART in EC decreases activation indices but does not appear to increase circulating CD4 T cell numbers nor do we know if it alters clinical outcomes. Thus, it is difficult to recommend or discourage a decision to start ART in the EC population but the authors lean toward treatment particularly in those EC whose activation indices are high and those who are progressively losing circulating CD4 T cell numbers. Biomarkers that can reliably predict loss of virologic control and immune failure are needed., Competing Interests: Co-author Michael M. Lederman is the Editor-in-Chief of Pathogens and Immunity., (© Pathogens and Immunity 2020.)

Background: Elite controllers (EC), a small subset of the HIV-positive population (< 1%), suppress HIV viremia below the limit of quantification of clinical viral load assays in the absence of antiretroviral therapy (ART). However, there is a paucity of longitudinal data detailing the viral and immune dynamics or HIV reservoir seeding during acute infection in individuals that go on to become Elite Controllers., Case Presentation: In this report, we describe a case of a 42 year old woman diagnosed during acute infection who rapidly and permanently suppressed her viremia in the absence of antiretroviral therapy (ART). Rapid antibody/antigen testing was either negative or equivocal during acute infection, despite subsequent viral load testing at that time point with 71,550 plasma HIV RNA copies/mL, making initial diagnosis challenging. The patient subsequently developed detectable anti-HIV antibodies and an increase in HIV-specific CD8+ T cell responses to overlapping subtype C HIV gag peptide; very low-level plasma viremia (0.84 RNA copies/mL) was detected by an ultrasensitive assay 2 years following infection. Subsequently, she was started on ART for multifocal furunculosis despite continued suppression of virus and stable CD4+ T cell counts. Following ART initiation, HIV specific antibody levels and CD8+ T cell responses increased, but no HIV DNA or RNA was able to be isolated from large numbers of peripheral blood CD4+ T cells., Conclusion: This case provides important information regarding the establishment of elite HIV control during acute infection and also demonstrates an increase in HIV-specific immune responses following ART despite undetectable peripheral blood cellular measures of HIV persistence. This case also highlights the challenges in diagnosing acute HIV infection without the use of viral load testing in this rare elite controller phenotype.

Background: We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background., Methods: HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined., Findings: Two HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/10 6 PBMCs in 2009 and 2015 respectively, at 1.2 copies/10 6 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIV KON , a primary isolate of his own CRF02&#95;AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-γ; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02&#95;AG variant in his partner. The patient and his partner were heterozygous for the CCR5ΔD32 deletion and shared HLA-B*07, C*07 non-protective alleles., Interpretation: This thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4 + T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4 + T cells, and individually SDF-1β, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1β, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4 + T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies. IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the exact mechanisms of how their immune responses control infection are not known. In this study, we identified five soluble immune signaling molecules (cytokines) in the blood that were higher in ECs than in subjects with typical chronic HIV infection. We demonstrated that these cytokines can activate CD4 + T cells, the target cells for HIV infection. Furthermore, these five EC-associated cytokines could change expression levels of intrinsic resistance factors, or molecules inside the target cell that fight HIV infection. This study is significant in that it identified cytokines elevated in subjects with a good immune response against HIV and defined potential mechanisms as to how these cytokines could induce resistance to the virus in target cells., (Copyright © 2017 American Society for Microbiology.)

It is widely accepted that effective human immunodeficiency virus (HIV) vaccines need to elicit a range of responses, including neutralising antibodies and T-cells. In natural HIV infections, immune responses to Gag are associated with lower viral load in infected individuals, and these responses can be measured against infected cells before the replication of HIV. Priming immune responses to Gag with DNA or recombinant Bacillus Calmette-Guérin (BCG) vaccines, and boosting with Gag virus-like particles as subunit vaccines or Gag produced in vivo by other vaccine vectors, elicits high-magnitude, broad polyfunctional responses, with memory T-cell responses appropriate for virus control. This review provides justification for the inclusion of HIV Gag in vaccine regimens, either as a transgene expressing protein that may assemble to form budded particles, or as purified virus-like particles. Possible benefits would include early control via CD8(+) T-cells at the site of infection, control of spread from the entry portal, and control of viraemia if infection is established.

Background: Emerging data relating to human immunodeficiency virus type 1 (HIV-1) cure suggest that vaccination to stimulate the host immune response, particularly cytotoxic cells, may be critical to clearing of reactivated HIV-1-infected cells. However, evidence for this approach in humans is lacking, and parameters required for a vaccine are unknown because opportunities to study HIV-1 reactivation are rare., Methods: We present observations from a HIV-1 elite controller, not treated with combination antiretroviral therapy, who experienced viral reactivation following treatment for myeloma with melphalan and autologous stem cell transplantation. Mathematical modeling was performed using a standard viral dynamic model. Enzyme-linked immunospot, intracellular cytokine staining, and tetramer staining were performed on peripheral blood mononuclear cells; in vitro CD8 T-cell-mediated control of virion production by autologous CD4 T cells was quantified; and neutralizing antibody titers were measured., Results: Viral rebound was measured at 28,000 copies/mL on day 13 post-transplant before rapid decay to <50 copies/mL in 2 distinct phases with t1/2 of 0.71 days and 4.1 days. These kinetics were consistent with an expansion of cytotoxic effector cells and killing of productively infected CD4 T cells. Following transplantation, innate immune cells, including natural killer cells, recovered with virus rebound. However, most striking was the expansion of highly functional HIV-1-specific cytotoxic CD8 T cells, at numbers consistent with those applied in modeling, as virus control was regained., Conclusions: These observations provide evidence that the human immune response is capable of controlling coordinated global HIV-1 reactivation, remarkably with potency equivalent to combination antiretroviral therapy. These data will inform design of vaccines for use in HIV-1 curative interventions., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Elite 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., Methods: For 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., Results: We 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%)., Conclusions: Elite controllers are hospitalized more frequently than persons with medically controlled HIV and cardiovascular hospitalizations are an important contributor., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Past genome-wide association studies (GWAS) involving individuals with AIDS have mainly identified associations in the HLA region. Using the latest software, we imputed 7 million single-nucleotide polymorphisms (SNPs)/indels of the 1000 Genomes Project from the GWAS-determined genotypes of individuals in the Genomics of Resistance to Immunodeficiency Virus AIDS nonprogression cohort and compared them with those of control cohorts. The strongest signals were in MICA, the gene encoding major histocompatibility class I polypeptide-related sequence A (P = 3.31 × 10(-12)), with a particular exonic deletion (P = 1.59 × 10(-8)) in full linkage disequilibrium with the reference HCP5 rs2395029 SNP. Haplotype analysis also revealed an additive effect between HLA-C, HLA-B, and MICA variants. These data suggest a role for MICA in progression and elite control of human immunodeficiency virus type 1 infection., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)