Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Background:Lopinavir/ritonavir (LPV/r)-dosed twice daily has demonstrated durable efficacy in antiretroviral-naive and protease inhibitor (PI) -experienced patients. Study M05-730 compared LPV/r tablets dosed once daily vs. twice daily in antiretroviral-naive subjects. Methods:Six hundred sixty-four subjects were randomized to LPV/r soft gel capsules (SGCs) once daily, SGC twice daily, tablets once daily, and tablets twice daily, all with tenofovir and emtricitabine once daily. At week 8, all SGC-treated subjects were switched to tablets, maintaining randomized dose frequency. The primary efficacy analysis used an intent-to-treat, noncompleter = failure approach to assess noninferiority of the LPV/r once-daily group compared with the twice-daily group. Results:At week 48, 77% of once-daily-dosed subjects vs. 76% of twice-daily-dosed subjects had HIV-1 RNA <50 copies per milliliter (P = 0.715; 95% confidence interval for difference: 5% to 8%). Response rates were numerically similar between the once-daily and twice-daily groups among subjects with baseline HIV-1 RNA ≥100,000 copies per milliliter (75% once daily vs. 74.6% twice daily; P > 0.999) or when analyzed by baseline CD4+ T-cell count (<50, 50 to <200, and ≥200 cells/mm3). Rates of discontinuation and adverse events, including diarrhea, were similar between arms. Among subjects with protocol-defined virologic rebound through week 48, no new PI resistance mutations were detected. Conclusions:At 48 weeks, the antiviral response in the LPV/r once-daily group was noninferior to the twice-daily group when coadministered with tenofovir and emtricitabine in antiretroviral-naive subjects. Efficacy was comparable between the once-daily and twice-daily groups regardless of baseline HIV-1 RNA or CD4+ T-cell count. Safety and tolerability of once-daily and twice-daily dosing was also comparable. No new PI resistance mutations were detected upon virologic rebound.

We conducted a prospective cohort study of 795 outpatients, many of whom were human immunodeficiency virus-infected men who have sex with men, to characterize risk of skin and soft-tissue infection (SSTI) associated with methicillin-resistant Staphylococcus aureus (MRSA) nares and perianal colonization. Multivariate analysis revealed that perianal colonization, drug use, and prior SSTIs were strongly associated with development of an SSTI. Of the patients who were colonized with MRSA at study entry, 36.7% developed an SSTI during the ensuing 12 months, compared with 8.1% of persons who were not colonized with MRSA.

BACKGROUND Spontaneous control of human immunodeficiency virus (HIV) infection has been documented in a minority of HIV-infected individuals. The mechanisms behind this outcome remain largely unknown, and a better understanding of them will likely influence future vaccine strategies. METHODS HIV-specific T cell and antibody responses as well as host genetics were examined in untreated HIV-infected patients who maintain comparatively low plasma HIV RNA levels (hereafter, controllers), including those with levels of < 50 RNA copies/mL (elite controllers, n = 64), those with levels of 50-2000 copies/mL (viremic controllers, n = 60); we also examined HIV-specific T cell and antibody responses as well as host genetics for patients with levels of >10,000 copies/mL (chronic progressors, n = 30). RESULTS CD8+ T cells from both controller groups preferentially target Gag over other proteins in the context of diverse HLA class I alleles, whereas responses are more broadly distributed in persons with progressive infection. Elite controllers represent a distinct group of individuals who have significantly more CD4 and CD8 T cells that secrete interferon-gamma and interleukin-2 and lower levels of HIV-neutralizing antibodies. Individual responses were quite heterogeneous, and none of the parameters evaluated was uniquely associated with the ability to control viremia. CONCLUSIONS Elite controllers are a distinct group, even when compared to persons with low level viremia, but they exhibit marked genetic and immunologic heterogeneity. Even low-level viremia among HIV controllers was associated with measurable T cell dysfunction, which has implications for current prophylactic vaccine strategies.

Background: Nonoccupational postexposure prophylaxis (NPEP) has been used to decrease HIV transmission after high-risk exposures. However, suboptimal adherence in completing the recommended 28-day course has resulted in prophylaxis failures. Fenway Community Health, the largest center caring for HIV-infected and high-risk men who have sex with men (MSM) in New England, began an NPEP program in 1997, initially using zidovudine-based regimens.Methods: Two phase 4 studies, using tenofovir DF regimens combined with either lamivudine or emtricitabine, were conducted. This paper evaluates the experience of those who used tenofovir-based NPEP regimens, comparing the subjects to historical controls who used zidovudine-containing regimens.Results: Between May 2004 and March 2005, 44 individuals who presented after high-risk sexual exposure were prescribed tenofovir DF/lamivudine for NPEP. Between March 2005 and March 2006, 68 individuals with 72 high-risk experiences received tenofovir DF/emtricitabine, and were compared to 122 historical controls who were prescribed 126 courses of zidovudine plus lamivudine between January 2000 and May 2004. Seventy-two percent of those who took tenofovir DF and emtricitabine, and 87.5% of the participants who took tenofovir DF and lamivudine, for NPEP completed their regimens as prescribed, whereas only 42.1% of those who took zidovudine plus lamivudine did so (P < 0.0001). Participants who took tenofovir DF-containing regimens were more likely to report diarrhea or abdominal discomfort; patients who took zidovudine-containing regimens were more likely to report nausea and vomiting, which was often severe enough to lead to product discontinuation.Conclusions: Tenofovir DF-containing regimens for NPEP are generally well tolerated with high completion rates. Tolerability and adherence compared favorably to zidovudine-containing regimens used previously. Tenofovir DF-containing regimens should be considered for PEP to enhance adherence and regimen completion.

Men who have sex with men (MSM) receiving non-occupational post-exposure prophylaxis (NPEP) to prevent HIV transmission completed interview-assisted questionnaires regarding high-risk behavior in the 6 months prior to NPEP and during the 28-day NPEP period. 21% of participants reported unprotected sex during NPEP, and 11% reported unprotected sex with HIV-positive or HIV status unknown partners. In univariate analyses, unprotected sex during NPEP was associated with prevention fatigue, depression, loss of loved ones to HIV, and a history of engagement with HIV/AIDS service organizations, e.g., receiving services from an HIV-related agency, donating money to HIV-related causes, and reading HIV-related magazines. Logistic regression analyses revealed that the strongest predictor of risk-taking during NPEP was HIV engagement. These data underscore the importance of combining chemoprophylaxis with behavioral interventions that support risk-reduction. Such interventions should not assume that those most engaged with HIV/AIDS service organizations are less likely to engage in risk behavior.

Context Researchers have recently identified multidrug-resistant USA300, a clone of community-acquired, methicillin-resistant Staphylococcus aureus (MRSA) that is resistant to multiple antibiotics. Contribution The authors demonstrate that the incidence of multidrug-resistant USA300 MRSA is highest in the areas of San Francisco where more male same-sex couples reside. The infection frequently manifests as an abscess or cellulitis in the buttocks, genitals, or perineum, and malemale sex was a risk factor. Caution Data were passively reported or retrospectively collected and are therefore subject to bias. Implication Multidrug-resistant USA300 MRSA infection is especially common among men who have sex with men. It might be sexually transmitted in this population. The Editors Infections caused by community-associated, methicillin-resistant Staphylococcus aureus (MRSA) have become a major public health threat. A single clone of community-associated MRSA, USA300, was not seen before 2000 but is now widely disseminated in 38 U.S. states, Canada, and 9 European Union countries (117). It can cause unusually severe disease, including necrotizing fasciitis, sepsis, endocarditis, and pneumonia (1823). Infections occur predominantly among healthy, community-dwelling persons who lack traditional risk factors for MRSA (9, 18, 2426). Whereas hospital-associated MRSA strains are resistant to multiple antimicrobial classes, USA300 and other community-associated MRSA strains are typically resistant to -lactams and 1 or 2 other drug classes. Older generic antimicrobials, such as clindamycin, tetracycline, or trimethoprimsulfamethoxazole, are recommended for treating less serious community-associated MRSA infections, such as uncomplicated skin and soft tissue infections (3, 27). However, increased use of these antimicrobials could drive the emergence of new subclones of community-associated MRSA that are multidrug resistant. Recently, Diep and colleagues (28) described a multidrug-resistant USA300 isolate that had accumulated multiple resistance genes, rendering it resistant to -lactams, fluoroquinolones, tetracycline, macrolide, clindamycin, and mupirocin. Two of the resistance genes from this isolate, ermC and mupAwhich determine constitutive resistance to macrolides, clindamycin, and mupirocinare carried on a large conjugative plasmid called pUSA03 (28). Researchers have identified clusters of infections due to multidrug-resistant USA300 in San Francisco and Boston (29, 30), which could complicate disease management and contribute to development of persistent or recurrent community-associated MRSA infections (31, 32). We report the incidence of multidrug-resistant USA300 in San Francisco and Boston among men who have sex with men, and we describe factors associated with its spread in this high-risk population, on the basis of 4 studies: a population-based survey to estimate the incidence and spatial clustering of multidrug-resistant USA300 in San Francisco; 2 clinic-based, cross-sectional studies to identify risk factors for multidrug-resistant USA300 infection; and a post hoc analysis of multidrug-resistant USA300 isolates previously collected from emergency departments (1). Methods Population-Based Survey We characterized MRSA isolates previously collected in a population-based survey of MRSA infections at 9 of the 10 medical centers serving San Francisco in 2004 to 2005 (Liu C, Graber CJ, Karr M, Diep BA, Basuino L, Schwartz BS, et al. A population-based study of the incidence and molecular epidemiology of methicillin-resistant-Staphylococcus aureus disease in San Francisco, 2004-5. In preparation). The medical centers used passive surveillance for MRSA; physicians submitted cultures to laboratories for identification of pathogens when patients presented with a disease that, in the physician's opinion, required culture. The 9 medical centers operate 4368 licensed hospital beds; the medical center that did not participate in the survey operates 59 licensed hospital beds. The participating medical centers initiated routine specimen collection between February and September 2004 and collected clinical MRSA specimens from unique patients (n= 3929) for 12 consecutive months. If a specimen was submitted from a patient for whom a sample was cultured earlier in the study period, we used the first specimen. We excluded 103 isolates because they came from patient nares and did not represent active infection. Of the remaining 3826 MRSA specimens, 2495 were from patients residing in San Francisco. The 3826 MRSA specimens were stratified by the medical center of origin and then by the month of specimen collection, and we used a random-number generator to select up to 8 MRSA specimens from each stratum. The stratified random sample comprised 801 nonduplicated MRSA specimens, and of these, 532 were recovered from patients residing in San Francisco. We calculated the incidence of multidrug-resistant USA300 infection in each city ZIP code on the basis of the 532 cases, and we used 2000 U.S. Census data (33) to test the association between disease incidence estimates and the proportion of male same-sex couples living in those ZIP codes. HIV ClinicBased Study We conducted a retrospective chart review of consecutive patients (n= 183) who had MRSA cultured from an infection site from January 2004 through June 2006 at the San Francisco General Hospital (SFGH) Positive Health Program, an outpatient HIV clinic that provides specialized HIV and AIDS care in San Francisco, California. Of the 183 specimens, 83 were collected between 1 February 2004 and 31 January 2005 as part of the population-based survey; these 83 specimens represented a subset of 1014 unique MRSA isolates identified from all SFGH sites in the population survey. Using a standardized instrument, we abstracted information about patients' demographic characteristics, male homosexual behavior, HIV viral load, CD4+ cell count, past culture-proven MRSA infection, past clinical presentation, and site of infection from medical records. We collected information about male homosexual behavior from the patient's clinic intake form (typically administered by a social worker), in which the patient was asked for self-identification of sexual behavior. If the clinic intake form was incomplete or missing, we classified a male patient as a man who has sex with men if an anal Papanicolaou (Pap) smear was performed at any time during his history at the clinic in the absence of indications other than anal receptive intercourse (screening anal Pap smear). Eight patients had missing sexual behavior data and no history of anal Pap smears; we classified them as men who do not have sex with men. Seven of these men had nonmultidrug-resistant USA300 infection, and 1 had a non-USA300 infection. Our estimates of risk for multidrug-resistant USA300 with malemale sex did not change meaningfully when these 7 patients with nonmultidrug-resistant USA300 infection were reclassified as occurring in men who have sex with men or when they were excluded from analyses (data not shown). We also compared the proportion of patients with multidrug-resistant USA300 infection in the HIV clinic with a subset of 91 MRSA cases randomly selected from the 1014 MRSA isolates identified from SFGH in the population-based study. Community Health ClinicBased Study We conducted retrospective chart reviews of 130 consecutive patients with MRSA infection treated at Fenway Community Health, Boston, Massachusetts, from April 2004 through March 2006. Fenway Community Health is a community-based organization that provides primary care to more than 10000 patients annually (34). Reports have noted that a large proportion of MRSA isolates recovered from skin and soft tissue infection sites of patients seen at Fenway Community Health were resistant to multiple antimicrobial agents (30, 31). Using the same standardized instrument developed for the SFGH HIV clinic study, we abstracted clinical data from medical records of each patient at Fenway Community Health. Among these patients, 3 with missing data on sexual behavior and no history of screening anal Pap smears were classified as men who do not have sex with men; these 3 patients had nonmultidrug-resistant USA300 infections. We genotyped the multidrug-resistant USA300 isolate of 1 clinic patient who reported malemale sex and frequent travel to and from the Castro District in San Francisco to see whether frequent travel by men who have sex with men between the East and West coasts facilitates the clonal spread of multidrug-resistant USA300. Emergency DepartmentBased Study Because the spread of multidrug-resistant USA300 is a potential public health threat, we investigated the distribution of multidrug-resistant USA300 in the general population of patients with community-associated MRSA infections. To this end, we conducted a post hoc analysis of 212 USA300 isolates collected by Moran and colleagues (1) in August 2004 from emergency departments in 11 U.S. cities. The study was approved by the University of California, San Francisco, Committee on Human Research and the institutional review board of Fenway Community Health; the institutions waived the informed consent process because the study involved retrospective chart reviews. Antimicrobial Susceptibility Testing We tested isolates for susceptibility to oxacillin, ciprofloxacin, erythromycin, tetracycline, clindamycin, trimethoprimsulfamethoxazole, gentamicin, vancomycin, linezolid, and mupirocin and interpreted the results in accordance with the Clinical and Laboratory Standards Institute guidelines (35). We performed inducible clindamycin resistance (D-zone test) by using the agar disk diffusion method in accordance with Clinical and Laboratory Standards Institute guidelines (35). Molecular Analysis We genotyped isolates by using pulsed-field gel electrophoresis after SmaI-macrorestriction digest of chromosomal DNA (36), spa typing of the pol

Large clinical trials have repeatedly proven the effectiveness of highly active antiretroviral therapy (HAART) in achieving virological suppression; however, subsequent increases in CD4 cell counts (i.e., immunological rebound) do not always follow. Thus, it remains unclear to what extent persons living with HIV/AIDS may expect significant increases in CD4 cell count upon HAART initiation, particularly outside of the highly structured environment of a clinical trial. We analyzed the patterns of CD4 and plasma viral load (PVL) change in 170 HIV-infected individuals who were ART naive and initiated HAART between 1997 and 2003. Immunological success (>50 CD4 cells/mm(3) increase) was evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Of individuals, 80% experienced a confirmed CD4 cell count increase of >50 cells/mm(3) after HAART initiation. Multivariate analysis showed that patients with pre-HAART PVL >or=100,000 copies/ml were more likely to achieve immunological success when compared with patients with baseline PVL <10,000 copies/ml, suggesting that individuals with the highest HIV viral load levels may benefit the most from HAART initiation. Future studies of immunological rebound are warranted to further define and characterize immune responses to HAART in diverse populations in order to optimize guidelines for initiation of treatment and assessment of successful responses.

Background. CD8+ T cells impact control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. In HIV-1 infection, persistent HIV-1 specific IFN-gamma+ CD8+ T cell responses are detected in the setting of disease progression, consistent with functional impairment in vivo. Recent data suggest that impaired maturation, as defined by the lineage markers CD45RA and CCR7, may contribute to a lack of immune control by these responses. Methodology/Principal Findings. We investigated the maturation phenotype of epitope-specific CD8+ T cell responses directed against HIV-1 in 42 chronically infected, untreated individuals, 22 of whom were "Controllers'' (median 1140 RNA copies/ml plasma, range, 50 to 2520), and 20 "progressors'' of whom had advanced disease and high viral loads (median 135,500 RNA copies/ml plasma, range 12100 to >750000). Evaluation of a mean of 5 epitopes per person revealed that terminally differentiated CD8+ T cells directed against HIV-1 are more often seen in HIV-1 Controllers (16/22; 73%) compared to HIV-1 progressors (7/20; 35%)(p = 0.015), but the maturation state of epitope-specific responses within a given individual was quite variable. Maturation phenotype was independent of the HLA restriction or the specificity of a given CD8+ T cell response and individual epitopes associated with slow disease progression were not more likely to be terminally differentiated. Conclusions/Significance. These data indicate that although full maturation of epitope-specific CD8+ T cell responses is associated with viral control, the maturation status of HIV-1 specific CD8+ T cell responses within a given individual are quite heterogeneous, suggesting epitope-specific influences on CD8+ T cell function.

To assess the prevalence of asymptomatic urethral gonorrhea and chlamydia men who have sex with men (MSM) living in greater Boston, 206 men attending routine medical appointments consented to urine-based chlamydia and gonorrhea screening using urine LCR amplification. Of those screened, 201 patients also completed a seven-question survey to assess sexual risk behaviors associated with urethral sexually transmitted infections. Less than 1% of the asymptomatic patients screened tested positive for urethral chlamydia; none tested positive for urethral gonorrhea. Forty-eight percent reported multiple sexual partners in the 30 days prior to screening, with HIV-infected patients reporting fewer partners and less unprotected insertive anal sex than HIV-uninfected patients. Almost 25% of patients screened used the Internet in the 30 days prior to screening to find a sexual partner. Internet use was associated with increased numbers of sexual partners in the 30 days prior to screening. Findings suggest that asymptomatic urethral chlamydia and gonorrhea may be uncommon in MSM living in the greater Boston area and that the recent rise in the prevalence of sexually transmitted infections may not be due to untreated asymptomatic infections. Increased awareness of STD symptoms among patients and medical providers is critical to timely diagnosis and treatment of STDs in MSM.

HIV primary care is determined by the intersection of the unique aspects of the infection and its treatment, the unique aspects of the populations affected by HIV, and the challenges of disease prevention and health maintenance in the general population. Any primary care provider may be called on to care for a patient living with HIV, and it is incumbent on all medical providers to become proficient in the management of this complex infection. This proficiency includes an awareness of local resources for referral, including medical and surgical specialists, mental health providers, and social service organizations. Given the complexity of HIV care in the twenty-first century and the potential for involvement of multiple consultants, the role of primary care provider is perhaps more critical for the HIV-infected patient than for the average patient.

Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8+ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8+ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8+ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8+ T cells, resulting from the preferential loss of high-avidity CD8+ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8+ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8+ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication.

Background. Treatment of acute human immunodeficiency virus type 1 ( HIV-1) infection may have unique immunologic, virological, and clinical benefits. However, the timing of treatment, optimal starting regimens, and expected response to therapy have not been defined.Methods. One hundred two subjects treated during acute and early HIV-1 infection were observed prospectively to determine the effect of time elapsed before initiation of therapy on time to virological suppression and absolute CD4(+) cell count. Subjects were divided into pre- and postseroconversion groups on the basis of HIV-1 antibody status at the time of initiation of treatment. Absolute CD4(+) cell counts were compared between these groups and with those of historical untreated persons who had experienced seroconversion. Potential predictors of time to virological suppression and CD4+ cell count at >= 12 months were assessed.Results. Ninety-nine ( 97%) of 102 subjects achieved virological suppression. The median time to suppression was 11.1 weeks ( 95% confidence interval, 9.4 - 14.9) and was independent of initial regimen. The mean CD4+ cell count at 12 months was 702 cells/mm(3) ( 95% confidence interval, 654 - 750 cells/mm(3)) and showed an increasing trend over 60 months. Treated subjects demonstrated a statistically significant gain in the CD4(+) cell count, compared with untreated historical control subjects, at >= 12 months. Comparable virological and immunologic outcomes were seen in the pre- and postseroconversion groups. Baseline virus load and nadir CD4(+) cell count predicted time to virological suppression and CD4(+) cell count at >= 12 months, respectively.Conclusions. Early treatment of HIV-1 infection is well tolerated and results in rapid and sustained virological suppression. Preservation of CD4(+) cell counts may be achieved with early therapy, independent of seroconversion status. Protease inhibitor - based and nonnucleoside reverse-transcriptase inhibitor - based regimens show comparable performance in tolerability, time to virological suppression, and CD4(+) cell count when used as a first regimen.

HLA-A3 and -A11 share similar peptide-binding motifs, however, it is unclear if promiscuous epitope presentation by HLA-A3 or HLA-A11 is associated with promiscuous TCR recognition. Here, we show that despite widespread cross-presentation of identical HIV-1 peptides in HIV-1-infected individuals expressing HLA-A3 or HLA-A11, peptides presented by HLA-A3 or HLA-A11 commonly exhibited clear immune distinctiveness with exclusive TCR recognition. Yet, using HLA-A3 and HLA-A11 tetramers for testing T cell cross-recognition of the HIV-1 Nef QK10 epitope, we observed in two study persons that specific CD8+ T cell populations were able to cross-recognize this peptide in the context of both HLA-A3 and HLA-A11. This cross-recognition was mediated by single cross-reactive TCRs, as shown by TCR sequencing in conjunction with TCR Vbeta chain immunostaining. In each cross-reactive cell population, multiple TCR beta chain variants were detected in the presence of only one TCR alpha chain variant. Thus, despite distinct TCR recognition of HLA-A3 or HLA-A11 presented HIV-1 peptides in the vast majority of cases, specific TCRs can cross-recognize their antigen in the context of both HLA-A3 and HLA-A11.

The present study sought to investigate the prevalence of hepatitis C virus (HCV) among men who have sex with men (MSM) seen at a community health center, and to examine risk factors associated with infection. The study population included 218 MSM who were screened for HCV infection during routine clinic visits from May through December, 2001. Eighty-four percent of those screened (n = 183) agreed to complete a self-report questionnaire assessing drug use, sexual practices, and medical history. Participants ranged in age from 22 to 54 years. The majority of participants (82%) self-identified as Caucasian and 35% were HIV-positive. Prevalence of HCV infection was 11.5%. Men infected with HCV were more likely than HCV uninfected men to be coinfected with HIV and hepatitis B, and to have a history of rectal or urethral gonorrhea. HCV-infected men were more likely to have seen blood on shared cocaine straws and to have used crack cocaine in the past 6 months. Overall, 12% of HCV-infected men reported no parenteral risk factors for HCV infection. HCV seropositivity was significantly associated with an aggregate score representing high-risk behavior in the past six months. HCV prevention and screening should target MSM engaging in high-risk sex. Conversely, HIV and sexually transmitted infection risk reduction interventions should be targeted at MSM with HCV.

Spontaneous and sustained ("elite," or aviremic) control of HIV infection (ie, maintaining HIV RNA to less than 50 copies/mL in the absence of therapy) appears to occur in approximately 1 in 300 HIV-infected persons, and represents a distinct phenotype among HIV-infected individuals. Through a recently established international collaboration called the HIV Controller Consortium, over 300 elite controllers have been identified and blood samples collected. These ongoing studies will not only examine the immune responses to HIV that elite controllers generate, but will also make use of a newly available approach to defining the genetic basis of disease. Specifically, the consortium is attempting to determine the genetic basis underlying spontaneous control by performing whole genome analysis scans together with functional immunology studies in a large population of elite controllers. The goal of these studies is to provide insights that will help define the crucial parameters present in persons who are able to control HIV infection, similar to the control most people have with Epstein-Barr virus and varicella, namely by holding the virus in check. These findings could assist in the development of vaccines and new therapies. This article summarizes a presentation on spontaneous control of HIV infection and its implications for vaccine development made by Bruce D. Walker, MD, at an International AIDS Society-USA Continuing Medical Education course in New York in March 2007. The original presentation is available as a Webcast at www.iasusa.org.

ABSTRACT Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTI) have become increasingly common. This study's objectives were to describe the clinical spectrum of MRSA in a community health center and to determine whether the use of specific antimicrobials correlated with increased probability of clinical resolution of SSTI. A retrospective chart review of 399 sequential cases of culture-confirmed S. aureus SSTI, including 227 cases of MRSA SSTI, among outpatients at Fenway Community Health (Boston, MA) from 1998 to 2005 was done. The proportion of S. aureus SSTI due to MRSA increased significantly from 1998 to 2005 (P < 0.0001). Resistance to clindamycin was common (48.2% of isolates). At the beginning of the study period, most patients with MRSA SSTI empirically treated with antibiotics received a beta-lactam, whereas by 2005, 76% received trimethoprim-sulfamethoxazole (TMP-SMX) (P < 0.0001). Initially, few MRSA isolates were sensitive to the empirical antibiotic, but 77% were susceptible by 2005 (P < 0.0001). A significantly higher percentage of patients with MRSA isolates had clinical resolution on the empirical antibiotic by 2005 (P = 0.037). Use of an empirical antibiotic to which the clinical isolate was sensitive was associated with increased odds of clinical resolution on empirical therapy (odds ratio = 5.91), controlling for incision and drainage and HIV status. MRSA now accounts for the majority of SSTI due to S. aureus at Fenway, and improved rates of clinical resolution on empirical antibiotic therapy have paralleled increasing use of empirical TMP-SMX for these infections. TMP-SMX appears to be an appropriate empirical antibiotic for suspected MRSA SSTI, especially where clindamycin resistance is common.

China is a region of the world with a rapidly spreading HIV-1 epidemic. Studies providing insights into HIV-1 pathogenesis in infected Chinese are urgently needed to support the design and testing of an effective HIV-1 vaccine for this population. HIV-1-specific T cell responses were characterized in 32 HIV-1-infected individuals of Chinese origin and compared to 34 infected caucasians using 410 overlapping peptides spanning the entire HIV-1 clade B consensus sequence in an IFN-gamma ELISpot assay. All HIV-1 proteins were targeted with similar frequency in both populations and all study subjects recognized at least one overlapping peptide. HIV-1-specific T cell responses clustered in seven different regions of the HIV-1 genome in the Chinese cohort and in nine different regions in the caucasian cohort. The dominant HLA class I alleles expressed in the two populations differed significantly, and differences in epitope clustering pattern were shown to be influenced by differences in class I alleles that restrict immunodominant epitopes. These studies demonstrate that the clustering of HIV-1-specific T cell responses is influenced by the genetic HLA class I background in the study populations. The design and testing of candidate vaccines to fight the rapidly growing HIV-1 epidemic must therefore take the HLA genetics of the population into account as specific regions of the virus can be expected to be differentially targeted in ethnically diverse populations.

Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8(+)-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8(+)-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8(+)-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.