For sotrastaurin-treated patients the absolute number of FoxP3+CD127low Tregs remained stable: median numbers were 23, 16 and 28 cells/μl pre-, 3 and 6 months after transplantation (Fig. 4b). In neoral-treated patients, the number of FoxP3+CD127low Tregs decreased significantly at month 3 but returned to levels pretransplantation at month 6 (median check details 12 and 18 cells/μl 3 and 6 months after transplantation, P = 0·008 for neoral 3 months versus pretransplantation (Fig. 4b). Trough levels of sotrastaurin correlated with Treg numbers: the AUC of trough levels at 0–3 months

correlated with the absolute number of FoxP3+CD127lowCD4+CD25high T regulatory cells at 3 months (n = 10, Pearson’s r = 0·65, P = 0·04). The AUC of trough levels at 0–6 months also AZD1208 supplier correlated with Treg numbers at 6 months (n = 10, Pearson’s r = 0·68, P = 0·03) (Fig. 5). The functional capacity of patients’ effector and regulator T cells was tested in MLR. Of two sotrastaurin- and two neoral-treated patients, the number of isolated CD4+CD25high T cells was insufficient to determine their inhibitory capacity at each timepoint. The proliferative response of effector CD25low cells in samples of three patients was <1000 cpm. Co-culture experiments with isolated CD4+CD25high Tregs in a 1 : 10 ratio were performed (n = 4 sotrastaurin and n = 6 neoral). We analysed whether

co-culture with Tregs and time after transplantation influenced the proliferation in sotrastaurin- versus neoral-treated patients. The inhibitory capacity of Tregs in sotrastaurin-treated patients

remained intact: the median percentages of inhibition by Tregs were 82% pretransplantation, 71% at 3 months and 67% at 6 months against donor cells (months 3 and 6, P > 0·05 due to small sample size) (Fig. 6). The protein kinase C inhibitor sotrastaurin is a novel, calcineurin-independent drug in autoimmune disease, oncology and clinical organ transplantation. Currently, the effect of sotrastaurin Chlormezanone on cell populations that control immune responses is unknown. We therefore investigated the number and function of regulatory T cells in samples of healthy volunteers and in renal allograft recipients during sotrastaurin treatment. First, we determined the IC50 of sotrastaurin in MLR to confirm previous reported findings: Evenou et al. have shown that sotrastaurin potently inhibited alloreactivity of mouse and human T cells [6]. In a two-way MLR performed with human T cells, the IC50 of sotrastaurin to inhibit [3H]-thymidine incorporation after 6 days was 37 nM. The studies by Matz et al. also revealed dose-dependent inhibition by sotrastaurin of carboxyfluorescein succinimidyl ester (CFSE)-labelled CD4+ T cells, after allogeneic stimulation [17]. In one-way MLR with irradiated stimulator cells, we demonstrated that sotrastaurin blocked alloreactivity dose-dependently (Fig. 1). In the high concentration of 250 ng/ml, the mean percentage of inhibition was 92%. The mean IC50 of sotrastaurin in our experiments was 89 nM.

Where indicated, mannan (Sigma-Aldrich) or L-arginin (Carl Roth, Germany) were added at a final concentration of 1 mg/mL or 1 mM, respectively. CFSE dilution profiles of CD4+ T cells were determined on day 3 by flow cytometry. Cells were washed once in FACS buffer (PBS/2% FCS/1 mg/mL sodium azide), incubated with anti-CD16/CD32-blocking Ab (2.4G2) for 5 min at Regorafenib in vitro room temperature, and stained with diluted Ab mixtures. The following mAb were purchased from eBioscience, unless otherwise indicated: PE-Cy5.5-labeled anti-CD4 (RM4-5), APC-labeled anti-mouse DO11.10 TCR (KJ1-26), APC-labeled anti-F4/80 (BM8), biotin-labeled anti-PD-L2 (122), biotin-labeled anti-PD-L1 (1-111A)

and APC-labeled streptavidin (SouthernBiotech, Birmingham, AL). Samples were acquired on a FACS Calibur or Canto II instrument (BD Immunocytometry Vorinostat datasheet Systems, San Jose, CA) and analyzed by FlowJo software (Treestar, Ashland, OR). RNA was isolated from 2×107 BMDM using the Total RNA isolation kit (Fluka, Buchs,

Switzerland). cDNA was generated using the Superscript III reverse transcription kit (Invitrogen). The PCR was performed with the following primer pairs: β-actin: fwd 5′-ATGGATGACGATATCGCT-3′, rev 5′-ATGAGGTAGTCTGTCAGGT-3′; Fizz1: fwd 5′-CCATAGAGAGATTATCGTGGA-3′, rev 5′-TGGTCGAGTCAACGAGTAAG-3′; Arginase1: fwd 5′-GTATGACGTGAGAGACCACG-3′, rev 5′-CTCGCAAGCCAATGTACACG-3′; iNOS: fwd 5′-GTTCTCAGCCCAACAATACAAGA-3′, rev 5′-CAGAGGGGTAGG CTTGTCTC-3′. RT-PCR were performed with the LigthCycler Machine (Roche Diagnostics, Mannheim, Germany) using the following conditions: 3 min denaturation at 94°C, 40 rounds of denaturation (30 s at 94°C), annealing (30 s at 58°C) and elongation click here (60 s at 72°C) followed by a denaturation step to determine the quality of the PCR reaction. Briefly, 100 μL supernatant of macrophage cultures were mixed with 100 μL Gries Reagent (Sigma-Aldrich) and OD550 was determined with a photometer (Ultrospec 3000, Pharmacia Biotech). The standard curve was generated with serial

dilutions of sodium nitrite (Sigma-Aldrich). Briefly, p-values were calculated with the Mann–Whitney U-test using the website http://elegans.swmed.edu/∼leon/stats/utest.cgi. p-Values<0.05 were considered statistically significant. The authors thank A. Bol and W. Mertl for animal husbandry and L. Cheng for providing B7-H1-deficient mice. This work was funded by the FöFoLe Program of the Medical Faculty of the University of Munich, by the Emmy Noether Program (Vo944/2) and the SFB 571 (project D8) of the Deutsche Forschungsgemeinschaft. Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers are published as ”Supporting Information”.

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“The prevalence of treated patients with end-stage renal disease (ESRD) has been increasing steadily in Japan. High ESRD prevalence could be explained by multiple factors such as better survival on dialysis therapy, luxury acceptance due to insurance system to cover dialysis therapy, and ‘truly’ high incidence and prevalence of chronic kidney disease (CKD). The growing elderly population

may also contribute to this trend. The Japanese Society of Nephrology estimated the prevalence of CKD stage 3 as 10.4%, 7.6% within the range of 50–59 mL/min per 1.73 m2 AZD1152-HQPA mouse in a screened population. Strong predictors of treated ESRD shown by using community-based screening programs and an ESRD registry in Okinawa are dip-stick-positive proteinuria and hypertension. Low glomerular filtration rate per se, which is often observed in the elderly population, is not

a significant predictor of developing ESRD unless associated with proteinuria. CKD is common in Japan and is expected to increase, particularly in the elderly population. Benefits of proteinuria screening and automatic reporting of estimated glomerular filtration rate on the incidence of ESRD remain to be determined. According to the annual report of the Japanese Society for Dialysis Therapy (JSDT), the prevalence of treated end-stage renal disease (ESRD) patients has been increasing for the past 20 years (Fig. 1).1 In the population aged 75 years and over, the prevalence is more than 0.5%. The incidence of ESRD is also increasing, particularly NU7441 supplier in those aged 75 years and over (Fig. 2). The main causes of ESRD incidence are diabetes mellitus (DM), chronic glomerulonephritis and nephrosclerosis. The incidence of DM is now more than 300 per million populations in those aged 65 years and over (Fig. 3). The mean age at start of dialysis therapy is over 65 years. There is a north (low) to south (high) gradient in the incidence and prevalence of ESRD without obvious explanation. L-gulonolactone oxidase The CKD prevalence seemed to be increasing in Japan. According to a community-based

study in Hisayama, the age-adjusted prevalence of CKD stage 3 and 4 was 4.1% in 1974, 4.8% in 1988 and 8.7% in 2002 in men, and 7.3% in 1974, 11.2% in 1988 and 10.7% in 2002 in women.2 This secular trend may be related to both genetic and environmental factors. Low birthweight, which is associated with lower nephron number, might develop DM and hypertension and therefore increase risk of ESRD.3 However, such data is not available in Japan. Lifestyle-related factors that are often associated with obesity and metabolic syndrome may have a role in the development and progression of CKD.4,5 Japan has a long history of universal screening systems including urine test for proteinuria and haematuria.6,7 It is not mandatory, however, so the fraction of people participating has been low at approximately 20–30%.

The major finding in our study was that variant-specific in vitro transcribed and translated long ZnT8 (268–369) proteins primarily displaced the corresponding specific ZnT8Ab variant, although the reciprocal permutation experiment showed displacement as well. These data suggest that the 325 variant is part of a conformation-dependent ZnT8Ab epitope, but one which is not exclusively controlled by the amino acid at

this position. A major finding was also that a 15-mer ZnT8 peptide was insufficient to define the conformation-dependent Selleckchem RAD001 epitope. Even though the short synthetic peptides appeared to increase autoantibody binding to some extent (Fig 3 lower panels), this may be the results from non-specific

binding. selleck kinase inhibitor Therefore, a competing peptide would require a certain length as the short ZnT8 (318–331) peptide variants did not compete with any of the variant-specific patient sera. On the other hand, competition with the long ZnT8W proteins revealed distinctly different patterns with the unique human sera selected for this study. It was noted that the ZnT8 Triplemix RBA, detecting conformation-dependent antibodies rather than the typical ELISA linear epitopes, was positive in only 6 of 12 mice. Indeed, only one mouse (M3-W in Fig. 2) showed ZnT8tripleAb reactivity that could be readily diluted. However, in ELISA, this mouse did not show the highest end-point titers against the short ZnT8 (R/W/Q) linear peptides (Fig. 2). Lack of serum precluded experiments to establish whether epitope-specific conformational antibodies, not detectable in ELISA, were generated in the 2-hydroxyphytanoyl-CoA lyase mice. Further studies immunizing mice with longer peptides

will be needed in attempts to generate single amino acid-specific antibodies. Such antibodies have been possible to generate against other antigens in the past [25-27]. The lack of recognition to the short ZnT8 peptides in the human ZnT8Ab sera supports previous studies that the ZnT8Ab are conformation dependent [4, 13]. However, it has previously not been reported that the Kd values are higher for proteins with the same epitope as the patient sera. Our data in Table 2 demonstrate lower Kd values, which correspond to higher dilutions of the variant-specific in vitro transcription translation long ZnT8 (268–369) proteins tested on its variant-specific patient serum. We believe it is an important finding that binding of ZnT8RAb-specific sera could be displaced with long cold ZnT8W protein and vice versa. This finding underscores the conclusion that a single amino acid is unable to solely control the epitope specificity. Other amino acids outside the immediate polymorphic 325 site would therefore be important to autoantibody epitope. Previously proposed residues were R332, E333, K336 and K340 (Fig.

This calls into question the applicability to the human situation of studies performed on the lower genital tract in animal models. In addition, the observed failure of HCl to substitute for lactic acid suggests the specificity of lactic acid, and not just an acidic pH, for IL-23 induction. Thus, experimental protocols as well as commercial products that attempt to acidify the vagina with acids other than lactic acid do not mimic the natural environment and may be less than ideal. The implication that lactic acid may specifically aid Cell Cycle inhibitor in immune defense

leads one to question currently held beliefs about vaginal health. Vaginal lactic acid production by both the underlying epithelium (Gross, 1961) and endogenous lactobacilli and other bacteria contribute

to the final lactic acid concentration. Individual differences in colonizing lactobacilli and other components of the vaginal flora, variations in the genetic background that influence glucose metabolism and unique MK 2206 environmental and dietary exposures would all be expected to result in variations in lactic acid production. We postulate that the extent of lactic acid production, and not bacterial hydrogen peroxide production, is a key component of the innate immune defense mechanisms at this site. A recent investigation using gene amplification technology has revealed that the major Lactobacillus sp. in asymptomatic North American women is Lactobacillus inners, a bacterium that does not produce hydrogen peroxide (Ravel et al., 2010). Another study has demonstrated that both cervicovaginal fluid and semen block any hydrogen peroxide-induced microbicidal activity (O’Hanlon et al., 2010). Further study of larger numbers of women is clearly warranted to confirm our findings as well as to help unravel the misconceptions that now exist about vaginal bacterial flora and innate defense mechanisms

at this anatomical site. It would also be of interest to determine whether other organic acids that are structurally related to lactic acid, and that may be present in the vagina, have similar immunological Methocarbamol effects. In this regard, it has been demonstrated that lactate, but not butyrate, acetate, dichloroacetate, citrate or malate, augments lipopolysaccharide-induced IL-2 production by murine splenic T cells (Roth & Droge, 1991). In females before puberty and after menopause, vaginal lactic acid levels are much reduced and vaginal pH is elevated. Whether this contributes to a possible increased susceptibility to gram-negative bacterial infections under these conditions is not known and is worthy of investigation. In general, mucosal infection favors the induction of the Th17 subset while intravenous infection is characterized by the induction of Th1 cells (Pepper et al., 2010). This suggests that antimicrobial immunity at mucosal surfaces is preferentially geared towards IL-23 and IL-17 induction and away from the production of Th1 lymphocyte-generated IFN-γ.

For example, antiretroviral drugs as either preexposure prophylaxis or treatment selleck compound of established infection have been examined

in mice with reconstituted human immune system components, and preexposure prophylaxis with these reagents has been shown to block rectal transmission [26, 32-34]. In addition, experimental therapies against HIV infection using either antiviral siRNA delivery to T cells, siRNA-mediated silencing of the CCR5 coreceptor and of viral proteins, or cyclin-dependent kinase blockade to inhibit viral replication have been successfully employed in these mouse models [35-37]. Thus mice with reconstituted human immune system components recapitulate HIV infection and can be used as a preclinical model for therapies against this viral infection. Besides HIV, infection with the human tumor virus EBV has been studied in this in vivo model of the human immune system [6, 38-40]. For these studies the viral strain B95–8 MK-1775 mw was used almost exclusively, which was originally isolated from a patient with symptomatic primary EBV infection, called infectious mononucleosis [41]. i.p. infection with increasing infectious doses of EBV leads to

asymptomatic persistent infection, lymphoproliferative disease, or even hemophagocytic lymphohistiocytosis [40, 42]. During persistent infection, B cells primarily harbor the virus and strong evidence exists for both latent EBV infection as well as a low level of lytic EBV replication [38]. These persistently infected B cells can be purified from EBV-carrying animals and cultured in vitro as immortalized lymphoblastoid cell lines. They express all eight latent EBV antigens in so-called latency type III. However, it is much less clear if other Liothyronine Sodium EBV latencies also develop in mice with reconstituted human immune system components, such as latency 0, which is found without

any EBV protein expression in memory B cells of healthy virus carriers; latency I, which is found in Burkitt’s lymphoma and homeostatic proliferating memory B cells in humans; and latency II, which is present in Hodgkin’s lymphoma and germinal center B cells in healthy EBV carriers [43]. Immunohistochemical studies provide some evidence to support the development of latencies 0, I, and II in reconstituted mice [44, 45]. However, false-negative immunohistochemistry for EBV gene products might erroneously suggest the presence of latency types other than latency III. Interestingly, EBV-encoded miRNAs are required to establish systemic persistent infection [46]. Furthermore, a latent nuclear antigen of the virus, called Epstein-Barr nuclear antigen 3B (EBNA3B), suppresses tumor formation in vivo [47].

Induced eosinophilia and mastocytosis are found in the intestinal tract of IL-5 Tg mice undergoing a primary N. brasiliensis infection and relatively few larvae or worms can be recovered (69,75,76). The intestinal-stage parasites recovered from IL-5 Tg mice generally fail to localize in the preferred anterior third of the duodenum, are smaller than those from WT hosts and produce few eggs (64). Wild-type FVB/N mice also support few intestinal N. brasiliensis

larvae or worms at any stage of a primary infection (77). In none of the many host strains and genetic variants used in our studies have we seen strong inflammatory responses in the lungs 24–48 h pi., when most of the larvae are present (65,69,75,77). Intense inflammatory responses are evident 4–6 days post-primary infection and these may be focused on a few remaining larvae or larval sheaths, although a component of this inflammation may also reflect physical damage to the tissues caused by click here larval migration (65). Much has been made of this later response by other researchers, but it is important to understand that most larvae have migrated from the lungs to the gut by the end

of day 3 and see more so at least in primary infections, it is not this stage of inflammation that is larvicidal or inhibitory to further development and colonization. Leucocytes are in fact very scarce in the lungs during the period when larvae are present, with just a small number of cells of macrophage-like appearance that are generally not closely associated with the parasite (65). The late pulmonary inflammatory response may be important for priming for adaptive

immunity and perhaps in limiting tissue damage, though the latter seems less likely. A strong inflammatory response with activation of potent effector cells in the lungs may be counterproductive for both parasite and host. It is worth noting that the means through which this early lung inflammation is prevented should provide Florfenicol useful insights reaching beyond parasite immunology. We have some evidence that eosinophils and other leucocytes that accumulate in the gut may damage parasites at this site (69), but N. brasiliensis larvae are probably most vulnerable to attack earlier in the migratory pathway. In primary infections of IL-5 Tg (65) and WT FVB/N mice (77) and in secondary infections of WT CBA/Ca, BALB/c and C57BL/6 mice (69,75,76), larvae are trapped or damaged in the pre-lung phase of the migratory pathway. In primary infections of IL-5 Tg hosts, significant numbers of larvae are either trapped in the skin or migration to the lungs is prevented or delayed (65). Larvae that do manage to migrate to the lungs of IL-5 Tg mice are significantly smaller and paler than those recovered from WT mice (65). Conversely, more larvae can be recovered from the lungs of the IL-5−/− and ΔdblGATA deletion mutant strains in both primary and secondary infections (69).

Ubiquitin-positive NCIs, which are evident in the degenerating lower motor neurons, have long been recognized as a characteristic feature of the cellular pathology. However, TDP-43 immunostaining may reveal positive neuronal and glial cytoplasmic inclusions (NCIs and GCIs) not only in the affected lower motor neuron nuclei but also in the other apparently normal non-motor neuron nuclei, indicating that SALS is a multisystem neuronal-glial proteinopathy of TDP-43 affecting a wide range of both neurons and glial cells in the CNS.[20] TDP-43

pathology is also evident in many patients with superoxide dismutase FK506 molecular weight 1 (SOD1)-unrelated familial ALS, in whom mutations within the TDP-43 gene (TARDBP) have been identified; interestingly, although

rare, TARDBP mutations have also been identified in patients with SALS.[21, 22] Based on these pathological and genetic findings, TDP-43 has been implicated as an important contributor to the pathogenesis of ALS. PolyQ diseases are inherited neurodegenerative disorders caused by expanded CAG repeats that encode abnormally long polyQ stretches in the disease proteins. The polyQ-positive NCIs and neuronal intranuclear inclusions (NIIs) are widespread in the CNS beyond the degenerative areas, indicating that the diseases are also multisystem neuronal proteinopathies.[23] TDP-43 pathology in the polyQ diseases was first reported in HD.[15] Unlike the neurodegenerative diseases showing TDP pathology mainly in the Depsipeptide molecular weight limbic system, patients with HD have TDP-43-positive NCIs in the neocortex, where many polyQ-positive inclusions are also observed. More recently, intermediate-length polyQ expansions

(27–33 Qs) in ataxin 2 (ATX2), the causative gene of SCA2, were reported to be a genetic risk factor for SALS.[16] In cases of HD, Schwab et al. have reported that TDP-43 was frequently colocalized with huntingtin in dystrophic neuritis Non-specific serine/threonine protein kinase and various intracellular inclusions, but not in intranuclear inclusions.[15] Recently, Tada et al. examined autopsied patients with genetically confirmed HD with SALS, and found that two different proteinaceous inclusions coexisted in a small number of neurons in the affected brain. However, the two disease proteins, huntingtin and TDP-43, were not co-localized within the inclusions, although the regional distributions of TDP-43-positive inclusions and expanded polyQ (1C2)-positive inclusions partly overlapped.[19] Biochemically, TDP-43 isoforms similar to those seen in SALS were observed in one of the patients examined.[19] In these cases of HD with SALS, it seems that two distinct pathological pathways may each affect the brain. It is tempting to speculate that “aging” may promote the deleterious effect of mutant huntingtin on motor neurons and on TDP-43. We have previously reported the occurrence of TDP-43 pathology in SCA3/MJD.

In

addition to TCR signals, interactions Y-27632 datasheet between multiple ligands and their receptors are essential for the optimal activation of T cells. Several members of the TNFR superfamily, particularly OX40, 4-1BB, CD27, CD30 and HVEM, have been shown to provide signals both early and late after encounter with antigen 3, 4. We have shown that TNFR2 functions as one of the earliest members of the TNFR superfamily and plays a critical role in lowering the threshold for T-cell activation and in providing survival signals during the early phase of the T-cell response 6–8. Despite TNFR2′s role in providing crucial signals for initial T-cell activation, we found that it plays a critical role in limiting the duration RO4929097 in vivo of T-cell responses by promoting AICD. This study also provides novel insight regarding the mechanism by which TNFR1 and TNFR2 regulate AICD. AICD-resistant TNFR2−/− CD8+ T cells expressed high levels of intracellular TRAF2. Furthermore, blocking activated WT CD8+ T cells with anti-TNFR2

antibodies also increased intracellular TRAF2 levels with associated increase resistance to AICD (Figs. 1C and 3A). That TRAF2 provides pro-survival signals is supported by the observation that T cells expressing a dominant negative form of TRAF2 are much more susceptible to TNF-α-mediated cell death 16. However, in our retroviral transfection studies, the overexpression of TRAF2 in WT CD8+ T cells only increased the percentage of live cells without affecting the percentage of apoptotic cells (Fig. 3B). In this study, retroviral transfection may not lead to sufficiently high levels of intracellular TRAF2 to effectively block AICD. By contrast, silencing of TRAF2 in activated TNFR2−/− CD8+ T cells rendered them as sensitive to AICD as activated WT CD8+ T cells (Fig. 4) providing clear evidence that TRAF2 is directly involved in regulating cell death and apoptosis Aldol condensation in activated CD8+ T cells. Previous studies showed that the TRAF1 proteins could associate with TNFR1 and TNFR2 upon TNF-α binding 20 and the elevated levels of TRAF1 in activated CD8+ T cells could inhibit TNFR2-induced TRAF2 degradation 21. However, we found that silencing endogenous TRAF1

expression in either activated WT or TNFR2−/− CD8+ T cells did not affect the number of dead cells and apoptotic cells (data not shown) indicating that TRAF1 did not play a significant role in regulating cell death and apoptosis in activated CD8+ T cells. Our results support the hypothesis that TNFR1 functions as a pro-survival receptor in activated CD8+ T cells in the absence of TNFR2. This hypothesis is supported by the following observations: (i) activated WT and TNFR2−/− CD8+ T cells produced similar amounts of TNF-α, (ii) blocking of TNFR2 in WT CD8+ T cells rendered them more resistant to AICD and (iii) blocking antibodies to TNF-α increased susceptibility of activated TNFR2−/− CD8+ T cells to AICD. We propose the following model for these observations.

HIV sexual transmission is very inefficient, and a number of biological factors are critical in determining whether an unprotected sexual exposure to HIV results in productive infection. This review will focus on ways in which biology, rather than behaviour,

may contribute to regional and racial differences in HIV epidemic spread. Specific areas of focus are viral factors, host genetics, and the impact of co-infections and host check details immunology. Considering biological causes for these racial disparities may help to destigmatize the issue and lead to new and more effective strategies for prevention. It was famously said by Kofi Annan that ‘in Africa, AIDS has a woman’s face’,1 but gender is by no means the most marked imbalance when it comes to the effects of HIV. While women now bear over half of the global HIV burden,2 it is only in the continent of Africa that women constitute the majority of infected persons. In contrast, there is a tremendous disparity in the effects of HIV along racial and ethnic lines that is apparent throughout the world. This imbalance is most marked at a continental level, given that approximately two-thirds of all HIV-infected persons are in Africa, but is also apparent within most regional subepidemics. The reasons underlying the racial and geographical imbalances

Adriamycin clinical trial in HIV prevalence are complex and have led to myths, stereotypes, stigma and discrimination that may impede the development of better HIV prevention tools and programs. As is the case for all sexually transmitted infections (STIs), socio-economic and cultural factors have been hypothesized to be critical contributors to HIV transmission selleck compound and increased HIV prevalence in Africa.3,4 Many of these sociocultural factors are potentially stigmatizing and include higher per-capita rates of commercial sex,5 increased partner exchange/concurrency,6,7 intimate partner violence,8–10 and traditions such as wife inheritance.11 There are data supporting the causal association of HIV with at least some of these factors, but

it is unfortunate that a focus on the cultural and behavioural aspects of HIV transmission tends to implicitly lay blame for infection on affected communities or individuals.12 While a discussion of the sociocultural associations of HIV is beyond the scope of this review, our goal is to emphasize that there may be other causes for the geographical and racial imbalances in HIV prevalence that are equally important. Specifically, our goal is to explore possible biological cofactors that may enhance vulnerability and contribute to the substantial global racial disparities in HIV prevalence. Our hope is that a better understanding of such cofactors may allow the development of new HIV prevention tools while reducing stigma. There are major racial and geographical disparities in HIV prevalence.