Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs.

Viremic controllers and elite controllers/suppressors maintain control over HIV-1 replication. Some studies have suggested that control is a result of infection with a defective viral strain, while others suggested host immune factors have a key role. Here we document two HIV-1 transmission pairs: one consisting of a patient with progressive disease and an individual who became an elite suppressor, and the second consisting of a patient with progressive disease and a viremic controller.

Prolonged control of replication-competent dual- tropic human immunodeficiency virus-1 following cessation of highly active antiretroviral therapy.

Background: While initiation of highly active antiretroviral therapy (HAART) during primary HIV-1 infection occasionally results in transient control of viral replication after treatment interruption, the vast majority of patients eventually experience a rebound in plasma viremia.

Results: Here we report a case of a patient who was started on HAART during symptomatic primary infection and who has subsequently maintained viral loads of < 50 copies/mL for more than nine years after the cessation of treatment. This patient had a high baseline viral load and has maintained a relatively high frequency of latently infected CD4(+) T cells.

CD4+ T cells from elite suppressors are more susceptible to HIV-1 but produce fewer virions than cells from chronic progressors.

Elite suppressors/controllers (ES) are HIV-1-infected individuals who maintain stable CD4(+) T-cell counts and viral loads of <50 copies/mL without antiretroviral therapy. Research has predominantly focused on immune factors contributing to the control of viral replication in these patients. A more fundamental question, however, is whether there are differences in the nature of CD4(+) T-cell infection in ES compared with viremic patients.

Viral suppression of multiple escape mutants by de novo CD8(+) T cell responses in a human immunodeficiency virus-1 infected elite suppressor.

Elite suppressors or controllers (ES) are HIV-1 infected patients who maintain undetectable viral loads without treatment. While HLA-B*57-positive ES are usually infected with virus that is unmutated at CTL epitopes, a single, dominant variant containing CTL escape mutations is typically seen in plasma during chronic infection. We describe an ES who developed seven distinct and rare escape variants at an HLA-B*57-restricted Gag epitope over a five year period.

Circulating monocytes are not a major reservoir of HIV-1 in elite suppressors.

Circulating HIV-1-infected monocytes have been identified in patients on highly active antiretroviral therapy and may represent an important barrier to viral eradication. The nature of these cells in HIV-1-infected patients who maintain undetectable viral loads and preserved CD4(+) T cell counts without antiretroviral therapy (known as elite controllers or elite suppressors [ES]) is unknown. We describe here infrequent recovery of proviral HIV-1 DNA from circulating monocytes relative to CD4(+) T cells in ES, despite permissiveness of these cells to HIV-1 viral entry ex vivo.

Sustained elite suppression of replication competent HIV-1 in a patient treated with rituximab based chemotherapy.

The mechanism of elite control of HIV-1 replication is not fully understood. While immunosuppression due to rituximab based chemotherapy has been associated with increased replication of HBV, CMV, and HIV-1, control of replication-competent HIV-1 was maintained in an elite controller/suppressor treated with a regimen that included vincristine, cyclophosphamide, prednisone, four rounds of plasmapheresis and ten cycles of rituximab. The data suggests that de-novo antibody responses do not play a significant role in the control of viral replication in these patients.

Unstimulated primary CD4+ T cells from HIV-1-positive elite suppressors are fully susceptible to HIV-1 entry and productive infection.

Elite controllers or suppressors (ES) are a group of HIV-1-infected individuals who maintain viral loads below the limit of detection of commercial assays for many years. The mechanisms responsible for this remarkable control are under intense study, with the hope of developing therapeutic vaccines effective against HIV-1. In this study, we addressed the question of the intrinsic susceptibility of ES CD4(+) T cells to infection.

Evolution of the HIV-1 nef gene in HLA-B*57 positive elite suppressors.

Elite controllers or suppressors (ES) are HIV-1 infected patients who maintain viral loads of < 50 copies/ml without antiretroviral therapy. CD8+ T cells are thought to play a key role in the control of viral replication and exert selective pressure on gag and nef in HLA-B*57 positive ES. We previously showed evolution in the gag gene of ES which surprisingly was mostly due to synonymous mutations rather than non-synonymous mutation in targeted CTL epitopes.

Prolonged control of an HIV type 1 escape variant following treatment interruption in an HLA-B*27-positive patient.

The HLA-B*27 allele is overrepresented in patients who control HIV-1 replication without antiretroviral therapy. CD8(+) T cell responses that target the immunodominant KK10 epitope in Gag are thought to play a major role in this control, and escape at R264 of KK10 is often associated with dramatic virologic breakthrough. We present a case in which an HLA-B*27-positive chronic progressor transmitted HIV-1 to an HLA-B*27-positive viremic controller who was temporarily on HAART, but who has since controlled viremia for over 4 years.

HIV-1 Gag evolution in recently infected human leukocyte antigen-B*57 patients with low-level viremia.

We studied viral evolution in five human leukocyte antigen (HLA)-B*57 patients recently infected with HIV-1. Escape mutations in HLA-B*57-restricted Gag epitopes were present at study entry in all patients, but were not associated with significant increases in viremia. Conversely, no new escape mutations in HLA-B*57-restricted epitopes or known compensatory mutations were detected in patients who experienced significant increases in viremia.

Control of HIV-1 in elite suppressors despite ongoing replication and evolution in plasma virus.

A subset of HIV-1-infected patients known as elite controllers or suppressors (ES) control the virus naturally. We have previously demonstrated sequence discordance between proviral and plasma gag clones in ES, much of which can be attributed to selective pressure from the host (J. R.

A case of seronegative HIV-1 infection.

Patients infected with human immunodeficiency virus type 1 (HIV-1) typically seroconvert within weeks of primary infection. In rare cases, patients do not develop antibodies against HIV-1 despite demonstrable infection. We describe here a human leukocyte antigen (HLA)-B*5802-positive individual who presented with acquired immune deficiency syndrome despite repeatedly negative HIV-1 antibody screening test results.

HIV-1 evolution following transmission to an HLA-B*5801-positive patient.

The human immunodeficiency virus type 1 (HIV-1)-specific immune responses of patients with the HLA-B*57/5801 alleles who spontaneously control viral replication serve as an important model for T cell-based HIV-1 vaccines. Determining the breadth of this response and the extent of virologic escape in primary infection in these patients is therefore critical. Here we document the development of mutations in 3 HLA-B*5801-restricted epitopes in gag, nef, and pol in an HLA-B*5801-positive patient who had a viral load of only 1159 copies/mL at day 167 after infection.

T cell dynamics and the response to HAART in a cohort of HIV-1-infected elite suppressors.

Elite controllers or suppressors are untreated human immunodeficiency virus type 1 (HIV-1)-infected patients who maintain undetectable viral loads. In this study, we show that most elite suppressors do not experience significant changes in T cell counts over a 10-year period. Interestingly, treatment of an elite suppressor with highly active antiretroviral therapy (HAART) led to a marked decrease in immune activation.

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.

Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro.

Natural killer (NK) cells are associated with the innate immune response and are important in many viral infections. Recent studies indicate that NK cells can control human immunodeficiency virus type 1 (HIV-1) replication. We studied the effect of NK cells on HIV-1 replication in a subpopulation of HIV-1-infected individuals termed elite suppressors (ES) or elite controllers.

Evidence of CD8+ T-cell-mediated selective pressure on human immunodeficiency virus type 1 nef in HLA-B*57+ elite suppressors.

Elite suppressors (ES) are human immunodeficiency virus type 1 (HIV-1)-infected patients who maintain viral loads of <50 copies/ml without treatment. The observation that the HLA-B*57 allele is overrepresented in these patients implies that HIV-1-specific CD8(+) T cells play a key role in suppressing viral replication. We have previously shown that while CD8(+) T-cell escape mutations are rarely seen in proviral Gag sequences in resting CD4(+) T cells from peripheral blood, they are present in every clone amplified from the low levels of free virus in the plasma of HLA-B*57(+) ES.