Pathological Role of Anti-CD4 Antibodies in HIV-Infected Immunologic Nonresponders Receiving Virus-Suppressive Antiretroviral Therapy.

Increased mortality and morbidity occur among human immunodeficiency virus (HIV)-infected patients in whom CD4+ T-cell counts do not increase despite viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 immunoglobulin G (IgG) were found in HIV-positive immunologic nonresponders (ie, HIV-positive individuals with CD4+ T-cell counts of ≤350 cells/µL), compared with levels in HIV-positive immunologic responders (ie, HIV-positive individuals with CD4+ T-cell counts of ≥500 cells/µL) and healthy controls. Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T-cell recovery. Furthermore, purified anti-CD4 IgG from HIV-positive immunologic nonresponders induced natural killer (NK) cell-dependent CD4+ T-cell cytolysis and apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. We also found that anti-CD4 IgG-mediated ADCC exerts greater apoptosis of naive CD4+ T cells relative to memory CD4+ T cells. Consistently, increased frequencies of CD107a+ NK cells and profound decreases of naive CD4+ T cells were observed in immunologic nonresponders as compared to responders and healthy controls ex vivo. These data indicate that autoreactive anti-CD4 IgG may play an important role in blunted CD4+ T-cell reconstitution despite effective ART.

Use of an Outreach Coordinator to Reengage and Retain Patients with HIV in Care.

It is well established that retention in high-quality care and regular visits with an HIV/AIDS provider improve outcomes for people living with HIV/AIDS (PLWHA). However, nationally and regionally in South Carolina, retention rates remain low. We piloted an outreach program focused on characterizing out of care (OOC) patients to identify PLWHA who were lost to care and attempt reengagement through phone call, letter, and home visit interventions. Primary outcomes were reengagement, defined as attendance to a clinic appointment, and retention in care, defined by the Health Resources and Services Administration (HRSA) definition (two visits at least 90 days apart in 2015). There were 1242 adult clinic patients in 2014. A total of 233 patients were included in the OOC cohort, according to the inclusion criteria. Of these 233, the outreach coordinator found that a majority of patients, 119 (51%), were lost to care. Reengagement was seen in 52 (44%) patients lost to care, and among those who reengaged, 26 (50%) were retained in care in 2015. This report represents one of few interventions that target reengagement for patients who are lost to care. The use of an outreach coordinator was successful in reengaging and retaining patients in care. It represents an uncomplicated intervention, functional within the current clinic design and available funding structure of the Ryan White grant. Poor engagement and retention in care continue to be significant problems among PLWHA with resultant poor clinical outcomes. Continued focus on new interventions to improve retention in care is necessary to improve clinical outcomes.

Actinomyces meyeri, a Common Agent of Actinomycosis.

BACKGROUND: Actinomyces, particularly Actinomyces israelii, may cause indolent, persistent infections or represent normal mucosal flora, leading to management dilemmas. MATERIALS AND METHODS: Prompted by a refractory Actinomyces meyeri infection complicating AIDS, clinical data for all Actinomyces isolates at our hospital laboratory since 1998 were analyzed. RESULTS: A total of 140 cases had a positive result for Actinomyces cultures. Of 130 cases with adequate follow-up, 36 (28%) cases had end-organ or disseminated disease treated with prolonged antibiotics or surgery or both (Group 1). A. meyeri was more common than A. israelii (33% versus 8%; P < 0.05) in Group 1, particularly thoracic infections. Another 56 (43%) cases were considered local pathogens, treated with drainage only or short-course antibiotics (Group 2). Another 38 (29%) cases were deemed commensals (Group 3). Immunosuppression was less frequent in Group 1 versus Group 2 or 3 (P = 0.05) and human immunodeficiency virus or AIDS was uncommon. Foreign bodies or devices (Group 1 versus Group 2 or 3, P = 0.003) and alcoholism (Group 1 versus Group 2 or 3; P = 0.03) were associated with actinomycosis. Isolates from the central nervous system and musculoskeletal sites were more often treated as definitive disease; skin, abdominal or pelvic or single blood culture isolates were more likely commensals (all P < 0.05). Disease progression or recurrence did not occur in Groups 2 and 3, whereas Group 1 had complex and variable courses, including 2 deaths. CONCLUSIONS: In the absence of disseminated or end-organ disease, avoiding prolonged therapy for Actinomyces isolates was not associated with adverse outcomes. Alcoholism or foreign bodies were associated with actinomycosis. A. meyeri may be a more common cause of actinomycosis than previously recognized.

Tobacco Use Patterns in a Southern US HIV Clinic.

OBJECTIVES: Smoking rates are two to three times higher among people living with HIV and AIDS compared with the general population, but the prevalence of tobacco use among this population in the Charleston, SC region has not been established. To understand cigarette use, previous quit attempts, historic use of cessation therapies, and interest in cessation, a quality improvement project was implemented to survey smoking behaviors among this population. METHODS: During January-May 2010, HIV-infected patients arriving to the Medical University of South Carolina Infectious Diseases clinic were asked to complete a survey. Clinical and sociodemographic data were collected and analyzed using χ(2), and one-way analysis of variance models. RESULTS: Of unduplicated clinic encounters, 514 (75%) of patients completed the smoking survey. Less than half of responders were current (205, 40%) or former (42, 8%) smokers, with smoking prevalence higher for Caucasian males. Among current smokers, 170 (85%) reported having ever attempted to quit with the majority making a quit attempt without medication therapy (143, 83%). Nearly half of all current smokers (97, 49%) reported an active interest in speaking with a physician about quitting. Smoking status did not have meaningful relationships with HIV biomarkers, even when stratified by race and gender. CONCLUSIONS: This study supports that high rates of smoking exist in the south among people living with HIV and AIDS and demonstrated a need for smoking cessation interventions among these patients. These data have potentiated the hiring of a clinical pharmacist to aid in implementation of smoking cessation therapies in a more systematic and formal way.

Key differences in B cell activation patterns and immune correlates among treated HIV-infected patients versus healthy controls following influenza vaccination.

BACKGROUND: There is increasing recognition of the role of B cell dysfunction in HIV pathogenesis, but little is known about how these perturbations may influence responses to vaccinations. METHODS: Healthy controls (n=16) and antiretroviral therapy (ART)-treated aviremic HIV-infected subjects (n=26) receiving standard-of-care annual influenza vaccinations were enrolled in the present study. Total bacterial 16S rDNA levels were assessed by quantitative polymerase chain reactions in plasma. Serologic responses were characterized by ELISA, hemagglutination inhibition assay (HI), and microneutralization, and cell-mediated responses were assessed by ELISPOT (antigen-specific IgG+ antibody-secreting cells (ASCs)) and flow cytometry at pre-vaccination (D0), day 7-10 (D7) and day 14-21 (D14) post-vaccination. RESULTS: Decreased peripheral CD4+ T cell absolute counts and increased frequencies of cycling and apoptotic B cells were found at baseline in HIV-infected subjects relative to healthy controls. In healthy controls, post-vaccination neutralizing activities were related to the frequencies of vaccine-mediated apoptosis and cycling of B cells, but not to CD4+ T cell counts. In patients, both baseline and post-vaccination neutralizing activities were directly correlated with plasma level of bacterial 16S rDNA. However, overall vaccine responses including antibody titers and fold changes were comparable or greater in HIV-infected subjects relative to healthy controls. CONCLUSION: B cell function correlates with measures of recall humoral immunity in response to seasonal influenza vaccination in healthy controls but not in ART-treated patients.

Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial.

The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1 + participants. Of 833 randomized participants, 71% in the dolutegravir + abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 copies per milliliter through W144 (P = 0.01). Superior efficacy was primarily driven by fewer discontinuations due to adverse events in the dolutegravir + abacavir/lamivudine arm [dolutegravir + abacavir/lamivudine arm, 16 (4%); efavirenz/tenofovir/emtricitabine arm, 58 (14%)] through W144 [corrected]. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + abacavir/lamivudine recipients through W144.

Humoral immune responses to Streptococcus pneumoniae in the setting of HIV-1 infection.

Streptococcus pneumoniae (pneumococcus) remains one of the most commonly identified causes of bacterial infection in the general population, and the risk is 30-100 fold higher in HIV-infected individuals. Both innate and adaptive host immune responses to pneumococcal infection are important against pathogen invasion. Pneumococcal-specific IgA antibody (Ab) is key to control infection at the mucosal sites. Ab responses against pneumococcal infection by B cells can be generated through T cell-dependent or T cell-independent pathways. Depletion of CD4+ T cells is a hallmark of immunodeficiency in HIV infection and this defect also contributes to B cell dysfunction, which predisposes to infections such as the pneumococcus. Two pneumococcal vaccines have been demonstrated to have potential benefits for HIV-infected patients. One is a T cell dependent 13-valent pneumococcal conjugate vaccine (PCV13); the other is a T cell independent 23-valent pneumococcal polysaccharide vaccine (PPV23). However, many questions remain unknown regarding these two vaccines in the clinical setting in HIV disease. Here we review the latest research regarding B cell immune responses against pneumococcal antigens, whether derived from potentially invading pathogens or vaccinations, in the setting of HIV-1 infection.

Plasmacytoid dendritic cells mediate synergistic effects of HIV and lipopolysaccharide on CD27+ IgD- memory B cell apoptosis.

UNLABELLED: The effects of heightened microbial translocation on B cells during HIV infection are unknown. We examined the in vitro effects of HIV and lipopolysaccharide (LPS) on apoptosis of CD27+ IgD- memory B (mB) cells from healthy controls. In vivo analysis was conducted on a cohort of 82 HIV+ donors and 60 healthy controls. In vitro exposure of peripheral blood mononuclear cells (PBMCs) to LPS and HIV led to mB cell death via the Fas/Fas ligand (FasL) pathway. Plasmacytoid dendritic cells (pDCs) produced FasL in response to HIV via binding to CD4 and chemokine coreceptors. HIV and LPS increased Fas expression on mB cells in PBMCs, which was dependent on the presence of pDCs and monocytes. Furthermore, mB cells purified from PBMCs and pretreated with both HIV and LPS were more sensitive to apoptosis when cocultured with HIV-treated pDCs. Blocking the interferon receptor (IFNR) prevented HIV-stimulated FasL production in pDCs, HIV-plus-LPS-induced Fas expression, and apoptosis of mB cells. In vivo or ex vivo, HIV+ donors have higher levels of plasma LPS, Fas expression on mB cells, and mB cell apoptosis than controls. Correspondingly, in HIV+ donors, but not in controls, a positive correlation was found between plasma FasL and HIV RNA levels and between Fas expression on mB cells and plasma LPS levels. This work reveals a novel mechanism of mB cell apoptosis mediated by LPS and HIV through the Fas/FasL pathway, with key involvement of pDCs and type I IFN, suggesting a role for microbial translocation in HIV pathogenesis. IMPORTANCE: This study demonstrates that lipopolysaccharide (LPS) and type I interferon (IFN) play an important role in memory B cell apoptosis in HIV infection. It reveals a previously unrecognized role of microbial translocation in HIV pathogenesis.

Microbial TLR Agonists and Humoral Immunopathogenesis in HIV Disease.

Although T cells are the primary and most-studied targets of the Human Immunodeficiency Virus (HIV), B cells, especially memory B lymphocytes, are also chronically depleted in the course of HIV disease. Although the lack of CD4+ T cell help may explain these deficiencies, intrinsic defects in B lymphocytes appear to contribute to B cell depletion and reduced antibody (Ab) production in the setting of HIV, especially of some antigens eliciting T cell-independent responses. The gut mucosal barrier is disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Toll-Like Receptor (TLR) agonists. The association of enhanced systemic levels of TLR agonists and B cell dysfunction in HIV disease is not understood. This review discusses the potential role of microbial TLR agonists in the B cell depletion, enhanced autoantibody production and impaired responses to vaccination observed in HIV-infected hosts. Increased microbial translocation in HIV infection may drive B cells to produce autoantibodies and increase susceptibilities of B cells to apoptosis through activation-induced cell death. Determining the mechanisms of B cell perturbations in HIV disease will inform the design of novel strategies of improve immune responses to vaccines, reduce opportunistic infections and slow disease progression.

Preventing neonatal transmission of herpes simplex virus.

Herpes simplex virus (HSV) infections are highly prevalent and may have devastating consequences if transmitted to newborns. The highest risk of transmission is when the mother has primary HSV infection (rather than recurrence of chronic infection) late in pregnancy. Clinicians should obtain a careful history, performing serologic testing and counseling as appropriate. Delayed diagnosis of neonatal HSV is associated with high mortality. Even with adequate treatment, permanent sequelae, such as cerebral palsy and developmental delay, may occur. Clinicians should develop prudent strategies to avoid primary HSV acquisition during pregnancy, and provide prophylaxis or treatment when indicated.

Sex, race, and geographic region influence clinical outcomes following primary HIV-1 infection.

BACKGROUND: It is unknown whether sex and race influence clinical outcomes following primary human immunodeficiency virus type 1 (HIV-1) infection. METHODS: Data were evaluated from an observational, multicenter, primarily North American cohort of HIV-1 seroconverters. RESULTS: Of 2277 seroconverters, 5.4% were women. At enrollment, women averaged .40 log10 fewer copies/mL of HIV-1 RNA (P < .001) and 66 more CD4(+) T cells/µL (P = .006) than men, controlling for age and race. Antiretroviral therapy (ART) was less likely to be initiated at any time point by nonwhite women and men compared to white men (P < .005), and by individuals from the southern United States compared to others (P = .047). Sex and race did not affect responses to ART after 6 months (P > .73). Women were 2.17-fold more likely than men to experience >1 HIV/AIDS-related event (P < .001). Nonwhite women were most likely to experience an HIV/AIDS-related event compared to all others (P = .035), after adjusting for intravenous drug use and ART. Eight years after diagnosis, >1 HIV/AIDS-related event had occurred in 78% of nonwhites and 37% of whites from the southern United States, and 24% of whites and 17% of nonwhites from other regions (P < .001). CONCLUSIONS: Despite more favorable clinical parameters initially, female HIV-1-seroconverters had worse outcomes than did male seroconverters. Elevated morbidity was associated with being nonwhite and residing in the southern United States.

CD8 T-cell proliferative capacity is compromised in primary HIV-1 infection.

Understanding the correlates of immunity that control HIV-1 infection is imperative to our understanding of HIV-1 disease and vaccine development. HIV-1-specific cytotoxic T lymphocytes are fundamental to the control of viremia; however, which T-cell repertoire components enact this control remains unclear. We hypothesize that polyfunctional HIV-1-specific CD8 T cells capable of viral control are present in most patients early in infection and these cells are distinguished by their ability to secrete interleukin (IL)-2 and proliferate. We examined HIV-1-specific CD8 T-cell proliferation and cytokine secretion in primary HIV-1 infection (PHI) using known HIV-1 cytotoxic T-cell epitopes to exclude CD4 bystander effect. We found that only a subset of patients with PHI demonstrated "CD4-independent" CD8 proliferation ex vivo. The remainder of the patients lacked HIV-1-specific CD8 T cells with proliferative capacity, even after the addition of exogenous IL-2. Among the proliferators, IL-2 production from the total HIV-specific CD8 T-cell population correlated with proliferation. Surprisingly, though, we did not routinely detect both IL-2 secretion and proliferative capacity from the same antigen-specific CD8 T cells. Thus, there are distinct and heterogeneous populations of CD8 T cells, phenotypically characterized by either proliferation or IL-2 secretion and few with dual capacity. Generation of these responses may be an important measure of HIV-1 control but are not universal after PHI. Furthermore, the heterogeneity of this population suggests that a simple measure of an effective vaccine response remains elusive.

The virologic and immunologic effects of cyclosporine as an adjunct to antiretroviral therapy in patients treated during acute and early HIV-1 infection.

Acute human immunodeficiency virus type 1 (HIV-1) infection is characterized by high levels of immune activation. Immunomodulation with cyclosporine combined with antiretroviral therapy (ART) in the setting of acute and early HIV-1 infection has been reported to result in enhanced immune reconstitution. Fifty-four individuals with acute and early infection were randomized to receive ART with 4 weeks of cyclosporine versus ART alone. In 48 subjects who completed the study, there were no significant differences between treatment arms in levels of proviral DNA or CD4(+) T cell counts. Adjunctive therapy with cyclosporine in this setting does not provide apparent virologic or immunologic benefit.

Modeling sequence evolution in acute HIV-1 infection.

We describe a mathematical model and Monte Carlo (MC) simulation of viral evolution during acute infection. We consider both synchronous and asynchronous processes of viral infection of new target cells. The model enables an assessment of the expected sequence diversity in new HIV-1 infections originating from a single transmitted viral strain, estimation of the most recent common ancestor (MRCA) of the transmitted viral lineage, and estimation of the time to coalesce back to the MRCA. We also calculate the probability of the MRCA being the transmitted virus or an evolved variant. Excluding insertions and deletions, we assume HIV-1 evolves by base substitution without selection pressure during the earliest phase of HIV-1 infection prior to the immune response. Unlike phylogenetic methods that follow a lineage backwards to coalescence, we compare the observed data to a model of the diversification of a viral population forward in time. To illustrate the application of these methods, we provide detailed comparisons of the model and simulations results to 306 envelope sequences obtained from eight newly infected subjects at a single time point. The data from 68 patients were in good agreement with model predictions, and hence compatible with a single-strain infection evolving under no selection pressure. The diversity of the samples from the other two patients was too great to be explained by the model, suggesting multiple HIV-1-strains were transmitted. The model can also be applied to longitudinal patient data to estimate within-host viral evolutionary parameters.

Gender differences in discontinuation of antiretroviral treatment regimens.

BACKGROUND: Reported reasons for change or discontinuation of antiretroviral therapy ([delta]ART) include adverse events, intolerability, and nonadherence. Little is known how reasons for [delta]ART differ by gender. METHODS: In a retrospective cohort study, rates and reasons for [delta]ART alterations in a large University-based HIV clinic cohort were evaluated. Logistic regression analyses were used to evaluate the relationship between reasons for [delta]ART and gender. Cox proportional hazard models were used to investigate time to [delta]ART. RESULTS: In total, 631 HIV-positive individuals were analyzed. Women (n = 164) and men (n = 467) were equally likely (53.0% and 54.4%, respectively) to discontinue treatment within 12 month of initiating a new regimen. Reasons for [delta]ART, however, were different based on gender--women were more likely to [delta]ART due to poor adherence [adjusted odds ratio (OR), 1.44; 95% confidence interval (CI): 0.85 to 2.42], dermatologic symptoms (adjusted OR, 2.88; 95% CI: 1.01 to 8.18), neurological reasons (adjusted OR, 1.82; 95% CI: 0.98 to 3.39), constitutional symptoms (adjusted OR, 2.23; 95% CI: 1.10 to 4.51), and concurrent medical conditions (adjusted OR, 2.03; 95% CI: 1.00 to 4.12). CONCLUSIONS: Although the rates of [delta]ART are similar among men and women in clinical practice, the reasons for treatment changes are different based on gender. The potential for unique patterns of adverse events and poor adherence among women requires further investigation.

Retroviruses and other latent viruses: the deadliest of pathogens are not necessarily the best candidates for bioterrorism.

HIV-1 (and other viral causes of latent, chronic infections) is not a likely candidate for bioterrorism. Scenarios resulting in the introduction of retroviral infections into a large population generally seem impractical and unpredictable as bioterrorist plots, especially relative to the frightening simplicity of deadly anthrax spores or smallpox virions. As evidenced in the above discussion, contaminating the blood supply would require a highly sophisticated plan resulting in effects of rather limited ultimate scope, and would have to evade an extremely effective screening process already in full force. Contaminating other agents given parenterally is also a potential concern, but again the virus has rather fastidious growth characteristics outside of the human host, and even if this could be accomplished it would presumably affect only a very limited number of targeted individuals. Finally, the idea of a kind of"sexual suicide bomber", an individual deliberately introduced into the community to spread a deadly infectious disease might be proposed. However, as discussed in this commentary, the impact of this rather implausible scenario would be substantially delayed, unreliable, and ultimately could be controlled through a heightened response of already existing public health mechanisms. Whereas HIV has resulted in the "perfect storm" of a devastating pandemic, a major cause of worldwide morbidity and mortality that is tremendously challenging to control, it does not match up very effectively with the Centers for Disease Control and Prevention (CDC) Category A definition of an ideal agent of bioterrorism. It is not easily spread through casual or incidental contact and does not cause a substantial immediate death toll. Instead it is spread only through sexual, parenteral, or maternal/fetal transmission, and generally requires a prolonged and variable clinical latency period prior to disease progression and death. The U.S. public health system is already reasonably well equipped to screen, test, and treat HIV infection (although there is undeniably a greater need for community outreach and education). New introduction of HIV infections in the community via a bioterrorism plot might result in a quantitative difference-but not a funda-mental shift in CDC testing and monitoring plans. Thus, HIV does not match up very effectively as a category B agent of bioterrorism. A growing number of antiviral drugs, increasingly tolerable and conveniently dosed, are making the concept of post-exposure (and even pre-exposure) prophylactic HIV therapy a feasible consideration in many circumstances. The high mutability and adaptability of HIV is a key to its success as a chronic, latent pathogen. These characteristics make vaccine and antiviral drug development an ever-present challenge. On the other hand, there are no data to suggest this complex virus could be eas-ily modified so that it would be more easily transmissible or more rapidly, predictably fatal; therefore, making it an unlikely category C agent as well. Indeed, research during the past decade suggests that HIV disease progression is largely dependent on a complex, individualized host/pathogen interaction rather than the presence of a universal viral trait or toxin. The very characteristics that make a universal vaccine or curative treatment for HIV/AIDS so difficult to achieve also make it a rather poor candidate to be predictably manipulated and wielded as a bioterrorist's weapon.

Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline.

OBJECTIVE: Compare the initial phases of virologic decay when acute/early and advanced HIV-infected adults are administered the same treatment regimen. DESIGN: Mathematical modeling of a previously completed prospective treatment pilot study involving treatment-naive patients with early and advanced immunosuppression. METHODS: We analyzed data from a treatment protocol in which 18 individuals with acute or recent HIV-1 seroconversion and six patients with advanced AIDS were administered the same four-drug antiretroviral regimen. Initial treatment responses were compared by fitting a mathematical model to frequent viral load measurements in order to calculate the first and second phase kinetics of viral clearance, and also by comparing viral load suppression over 24 weeks. Patients were also comprehensively compared in terms of protease inhibitor drug levels, HIV-specific immune responses at baseline, and the presence of drug resistance-conferring mutations. RESULTS: There was no statistically meaningful difference in first phase clearance of comparable high-level viremia in the two groups, whether protease inhibitor levels were inserted into the model or 100% antiviral drug effectiveness was assumed. In contrast, acute/early patients had inferior sustained responses than advanced patients, reflecting erratic adherence. CONCLUSIONS: Despite many years of intervening immune destruction, the initial virologic decay on therapy appears to be the same at the extremes of the HIV disease spectrum.

Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection.

The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.

The virologic, immunologic, and clinical effects of interleukin 2 with potent antiretroviral therapy in patients with moderately advanced human immunodeficiency virus infection: a randomized controlled clinical trial--AIDS Clinical Trials Group 328.

BACKGROUND: Interleukin 2 (IL-2) administration increases CD4 counts in persons with higher counts. This study investigated persons with moderately advanced human immunodeficiency virus infection receiving highly active antiretroviral therapy (HAART). METHODS: Two hundred four patients with CD4 T-cell counts from 50/microL to 350/microL who were treatment naive or had been treated only with reverse transcriptase inhibitors began a specified protease inhibitor HAART regimen. Virologic responders (< or =5000 copies/mL) at 12 weeks were randomized to open-label continuous-infusion IL-2 (IV IL-2), subcutaneous IL-2 (SC IL-2), or HAART alone. Thirty were not randomized and 15 enrolled in a substudy, leaving 159 for analysis. Subjects continued HAART alone for 72 weeks (n = 52) or with IV IL-2 (n = 53) or SC IL-2 (n = 54) for 5 days every 8 weeks. The IV IL-2 subjects could switch to SC IL-2 if their CD4 T-cell count increased by 100/microL or by 25%. RESULTS: Patients receiving IV or SC IL-2 had greater increases in CD4 cell counts. At week 84, median increases were 459/microL, 312/microL, and 102/microL. Increases of greater than 50% at week 60 (primary end point) were achieved in 39 patients (81%) and 32 (67%) in the IV and SC IL-2 arms, respectively, compared with 13 (29%) in the HAART arm (P<.001 for both). Treatment with IL-2 did not increase plasma human immunodeficiency virus RNA levels. There were fewer new AIDS-defining events in the IV (P = .006) and SC (P = .03) IL-2 groups than in the HAART group (0, 1, and 7, respectively). Drug-related adverse events were more frequent with IL-2 treatment. CONCLUSION: Addition of IL-2 to HAART can significantly expand CD4 T-cell counts in moderately advanced human immunodeficiency virus infection, without loss of virologic control.