CTLA-4 blockade induces a microglia-Th1 cell partnership that stimulates microglia phagocytosis and anti-tumor function in glioblastoma.

The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNγ blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.

CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell trans-infection.

HIV-1 frequently escapes from CD8 T cell responses via HLA-I restricted adaptation, leading to the accumulation of adapted epitopes (AE). We previously demonstrated that AE compromise CD8 T cell responses during acute infection and are associated with poor clinical outcomes. Here, we examined the impact of AE on CD8 T cell responses and their biological relevance in chronic HIV infection (CHI). In contrast to acute infection, the majority of AE are immunogenic in CHI. Longitudinal analyses from acute to CHI showed an increased frequency and magnitude of AE-specific IFNγ responses compared to NAE-specific ones. These AE-specific CD8 T cells also were more cytotoxic to CD4 T cells. In addition, AE-specific CD8 T cells expressed lower levels of PD1 and CD57, as well as higher levels of CD28, suggesting a more activated and less exhausted phenotype. During CHI, viral sequencing identified AE-encoding strains as the dominant quasispecies. Despite increased CD4 T cell cytotoxicity, CD8 T cells responding to AE promoted dendritic cell (DC) maturation and CD4 T cell trans-infection perhaps explaining why AE are predominant in CHI. Taken together, our data suggests that the emergence of AE-specific CD8 T cell responses in CHI confers a selective advantage to the virus by promoting DC-mediated CD4 T cell trans-infection.

Induction and Quantification of Excitability Changes in Human Cortical Networks.

How does human brain stimulation result in lasting changes in cortical excitability? Uncertainty on this question hinders the development of personalized brain stimulation therapies. To characterize how cortical excitability is altered by stimulation, we applied repetitive direct electrical stimulation in eight human subjects (male and female) undergoing intracranial monitoring. We evaluated single-pulse corticocortical-evoked potentials (CCEPs) before and after repetitive stimulation across prefrontal (n = 4), temporal (n = 1), and motor (n = 3) cortices. We asked whether a single session of repetitive stimulation was sufficient to induce excitability changes across distributed cortical sites. We found a subset of regions at which 10 Hz prefrontal repetitive stimulation resulted in both potentiation and suppression of excitability that persisted for at least 10 min. We then asked whether these dynamics could be modeled by the prestimulation connectivity profile of each subject. We found that cortical regions (1) anatomically close to the stimulated site and (2) exhibiting high-amplitude CCEPs underwent changes in excitability following repetitive stimulation. We demonstrate high accuracy (72-95%) and discriminability (81-99%) in predicting regions exhibiting changes using individual subjects' prestimulation connectivity profile, and show that adding prestimulation connectivity features significantly improved model performance. The same features predicted regions of modulation following motor and temporal cortices stimulation in an independent dataset. Together, baseline connectivity profile can be used to predict regions susceptible to brain changes and provides a basis for personalizing brain stimulation.SIGNIFICANCE STATEMENT Brain stimulation is increasingly used to treat neuropsychiatric disorders by inducing excitability changes at specific brain regions. However, our understanding of how, when, and where these changes are induced is critically lacking. We inferred plasticity in the human brain after applying electrical stimulation to the brain's surface and measuring changes in excitability. We observed excitability changes in regions anatomically and functionally closer to the stimulation site. Those in responsive regions were accurately predicted using a classifier trained on baseline brain network characteristics. Finally, we showed that the excitability changes can potentially be monitored in real-time. These results begin to fill basic gaps in our understanding of stimulation-induced brain dynamics in humans and offer pathways to optimize stimulation protocols.

HIV-1-Specific CD8 T Cells Exhibit Limited Cross-Reactivity during Acute Infection.

Prior work has demonstrated that HIV-1-specific CD8 T cells can cross-recognize variant epitopes. However, most of these studies were performed in the context of chronic infection, where the presence of viral quasispecies makes it difficult to ascertain the true nature of the original antigenic stimulus. To overcome this limitation, we evaluated the extent of CD8 T cell cross-reactivity in patients with acute HIV-1 clade B infection. In each case, we determined the transmitted founder virus sequence to identify the autologous epitopes restricted by individual HLA class I molecules. Our data show that cross-reactive CD8 T cells are infrequent during the acute phase of HIV-1 infection. Moreover, in the uncommon instances where cross-reactive responses were detected, the variant epitopes were poorly recognized in cytotoxicity assays. Molecular analysis revealed that similar antigenic structures could be cross-recognized by identical CD8 T cell clonotypes mobilized in vivo, yet even subtle differences in a single TCR-accessible peptide residue were sufficient to disrupt variant-specific reactivity. These findings demonstrate that CD8 T cells are highly specific for autologous epitopes during acute HIV-1 infection. Polyvalent vaccines may therefore be required to provide optimal immune cover against this genetically labile pathogen.

HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses.

Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1) exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP) in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE) or its non-adapted (NAE) version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001). However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001). CD4+ T cell responses in patients with acute HIV infection (AHI) demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

Laser interstitial thermal therapy: A first line treatment for seizures due to hypothalamic hamartoma?

Successful treatment of hypothalamic hamartoma (HH) can result in the resolution of its sequelae including epilepsy and rage attacks. Risks and morbidity of open surgical management of this lesion have motivated the development of laser interstitial thermal therapy (LITT) as a less invasive treatment approach to the disease. Although overall morbidity and risk would appear to be lower, complications related to LITT therapy have been reported, and the longer-term follow-up that is now possible after initial experience helps address the question of whether LITT provides equivalent efficacy compared to other treatment options. We conducted a retrospective analysis of clinical outcomes in eight patients undergoing LITT for HH at our center using the Visualase/Medtronic device. Five patients had refractory epilepsy, one had rage attacks, and two had both. We also compared the published seizure-free outcomes over time and the complication rates for different interventional approaches to the treatment of epilepsy due to HH including open craniotomy, neuroendoscopic, radiosurgical, and radiofrequency approaches. With a mean follow-up of 19.1 months in our series of eight patients, six of seven epilepsy patients achieved seizure freedom, whereas the one patient with rage attacks only did not have improvement of his symptoms. A length of hospital stay of 2.6 days reflects low morbidity and rapid postoperative recuperation with LITT. Considering other reported series and case reports, the overall published seizure freedom rate of 21 of 25 patients is superior to published outcomes of HH cases treated by stereotactic radiosurgery (SRS), craniotomy, or neuroendoscopy, and comparable to radiofrequency ablation. The cumulative experience of our center with other published series supports relatively lower operative morbidity than more invasive approaches and efficacy that is as good or better than open craniotomy procedures and SRS. Although morbidity appears to be lower than other open approaches, complications related to LITT and their avoidance should be considered carefully.

Spectrum of pneumococcal serotype 11A variants results from incomplete loss of capsule O-acetylation.

Streptococcus pneumoniae is a significant bacterial pathogen that expresses >90 capsule serotypes. Conventional serotyping methods assume that each serotype is a genetically and antigenically distinct entity; however, recent investigations have revealed pneumococcal isolates that cannot be unambiguously serotyped because they share the properties of more than one serotype. Here, we employed a novel serotyping method and NMR spectroscopy to examine clinical isolates sharing properties of serotypes 11A and 11E. These ambiguous clinical isolates were provisionally named 11A variant (11Av) isolates. Serotype 11A pneumococci characteristically express capsule ß-galactose-6-O-acetylation (ßGal6OAc) mediated by the capsule synthesis gene wcjE, while 11E strains contain loss-of-function mutations in wcjE and completely lack the expression of ßGal6OAc. Although 11Av isolates also contained mutated wcjE alleles, 11Av clinical isolates were composed of antigenically homogeneous bacteria expressing reduced amounts of 11A-specific capsule antigen. NMR data confirmed reduced but detectable amounts of ßGal6OAc on 11Av capsule polysaccharide. Furthermore, the transformation of strains with wcjE alleles from 11Av strains was sufficient to restore partial ßGal6OAc in an 11E background. We conclude that, instead of being distinct entities, serotypes 11A and 11E represent two extremes of an antigenic spectrum resulting from variable capsule O-acetylation secondary to heterologous wcjE mutations. These findings challenge whether all clinically relevant pneumococci can be definitively categorized into distinct serotypes.

Time to treatment for patients receiving BCS in a public and a private university hospital in Atlanta.

Delays in treatment for breast cancer can lead to poorer patient outcome. We analyzed time to treatment among female patients receiving breast-conserving surgery in two different hospital settings, public versus private. Retrospective chart review revealed 270 patients diagnosed during 2004-2008. Three consecutive time intervals were defined (Initial abnormal imaging [I] to core biopsy [II] to surgery /pathology staging [III] to oncology evaluation for adjuvant treatment). Multivariate analyses investigated hospital type and demographic factors. Overall median treatment time was 83 days, Interval II accounting for the longest (43 days). Only 55% of patients received the entire spectrum of care within 90 days; for each consecutive 30-day interval, percentages varied dramatically: 80.7%, 31.1%, and 68.9%.Public hospital patients experienced longer overall time to treatment than private patients (94 versus 77 days, p < 0.001); these differences persisted throughout the intervals. Longer wait times were experienced by African Americans versus Caucasians (89 versus 64 days, p = 0.003), unmarried versus married patients (93 versus 70 days, p < 0.001), and Medicaid-insured patients, p < 0.001. In multivariate analyses, hospital type, race, marital status, and insurance predicted timely treatment within one or more intervals. For patients undergoing breast-conserving therapy, time to treatment differs between private and public settings. However, barriers to timely treatment arise from both system-based issues and patient socio-demographic factors. Studies are needed to evaluate and intervene on this intricate connection.

Microsurgical Management of Complex Hypothalamic Hamartomas in the Era of Minimally Invasive Therapy: A Case Series and Narrative Review.

BACKGROUND: There has been a paradigm shift in the management of hypothalamic hamartoma (HH) from traditional microsurgical techniques to less invasive alternatives. However, large and extensive HH may fail to respond to these therapies, necessitating craniotomies. METHODS: All patients who underwent microsurgical resection of a complex HH by the 2 senior authors from 2011 to 2021 were included. Charts were retrospectively reviewed and demographic, clinical, imaging, and outcome data were recorded. RESULTS: Eight patients (mean age, 7 years) were included. Two had failed previous treatments. All 7 presented with gelastic seizures and cognitive dysfunction, 6 showed central precocious puberty, and 3 had behavioral problems. The mean lesion size was 21.6 mm and all had interpeduncular extension, 5 had intraventricular extension (Delalande type I, 3; type III, 4; type IV, 1). A frontotemporal orbitozygomatic approach with optic nerve decompression was used in all patients, supplemented by another approach in 3 (endoscopic transventricular, 3; transcallosal, 1). Gross total resection was achieved in 6 patients and subtotal resection in 2. Transient complications occurred in 3 patients (37.5%): self-limited sodium imbalance (n = 3), subdural hygroma (n = 2). Permanent complications occurred in 2 patients (25%): perforator infarct (n = 1) and short-term memory loss (n = 1). All patients experienced seizure resolution with preserved hypothalamic-pituitary axis function. After a mean follow-up of 41 months (range, 2-66 months), 7 patients remained seizure free, and 1 had rare seizures. Cognitive and behavioral symptoms improved in all patients. CONCLUSIONS: For large HH with interpeduncular extension, microsurgery via the frontotemporal orbitozygomatic approach is a safe and highly effective treatment modality.

Lessons Learned Using a High-Definition 3-Dimensional Exoscope for Spinal Surgery.

BACKGROUND: The operative microscope has significantly advanced modern neurosurgical spine surgery but continues to be limited by high costs, suboptimal optics, poor ergonomics, and difficulties with maneuverability. We believe the novel 4K high-definition (4K-HD) 3-dimensional (3D) exoscope (EX), may improve the surgical corridor through advancements in illumination, ergonomics, magnification, and depth of field and has the potential to be utilized in neurosurgical education and training. OBJECTIVE: To evaluate the surgical potential of a novel 3D EX system in spinal surgery. METHODS: Retrospective analysis over 6 mo of all patients who have undergone spinal surgery at Northwell Health using the 3D EX. Nuances of surgical theater positioning, advantages/disadvantages of the EX and clinical sequelae of the patients were analyzed. RESULTS: All 10 patients who underwent spinal surgery utilizing the EX experienced excellent surgical and clinical outcomes without complications. The low-profile EX allowed for excellent operative corridors and instrument maneuverability. The large monitor also resulted in an immersive surgical experience, and gave team members the same 3D vision as the operator. CONCLUSION: This study demonstrates the feasibility of utilizing the 3D 4K-HD EX system and highlights potential technical assets of this novel technology in regard to optics, ergonomics, and maneuverability. Further clinical research is needed to examine the clinical effectiveness of the EX system for different surgical approaches through quantitative methodology.

Technical Aspects and Operative Nuances Using a High-Definition 3-Dimensional Exoscope for Cerebral Bypass Surgery.

BACKGROUND: Cerebral bypass operation is a technically challenging operation that requires excellent surgical visibility and efficient ergonomics to minimize complications and maximize successful revascularization. Despite the operative microscope's utilization for the past two generations, there remains a need for continued improvement in operative visualization and surgical ergonomics. OBJECTIVE: To report the positives and negatives of our initial experience using a novel 4 K high-definition (4K-HD) 3-dimensional (3D) exoscope (EX) for cranial bypass surgery. METHODS: A retrospective review over 6 mo was performed of all patients who have undergone cerebral bypass surgery at a single institution using the 4K-HD 3D EX. Advantages and disadvantages of the EX and clinical outcome of the patients were assessed. RESULTS: A total of 5 patients underwent cerebral EC-IC bypass surgery with no EX-related complications and successful revascularization. The lightweight design of the EX allowed for easy instrument maneuverability as well as uncomplicated surgical set up in the operating room. The assistance of the cosurgeon was significantly more efficient compared to that of the operating microscope. The large monitor allowed for an immersive, collaborative, and valuable educational surgical experience. CONCLUSION: Using the EX for cerebral bypass surgery, with 3D ultra-high-definition optics, enhancements of ergonomics, and improved training, we believe that the 3D 4K-HD EX may represent the next generation of operative scopes in microneurosurgery.

Early Epidural Blood Patch to Treat Intracranial Hypotension after Iatrogenic Cerebrospinal Fluid Leakage from Lumbar Tubular Microdiscectomy.

Management of cerebrospinal fluid (CSF) leak during minimally invasive lumbar tubular microdiscectomy poses challenges unique to the surgical approach. Primary repair can be limited via tubular retractor systems, and onlay graft and dural sealant are often the treatment of choice intraoperatively. Postoperative persistent CSF leak may lead to intracranial hypotension (IH) and positional headaches. Early epidural blood patch (EBP) efficacy in the treatment of spinal CSF leaks of both spontaneous and iatrogenic origin is well-established in numerous studies. However, there is no consensus on treatment of persistent IH symptoms for patients undergoing lumbar tubular microdiscectomy. We describe the clinical courses of two patients who were treated with early EBP for IH symptoms following CSF leak during tubular microdiscectomy. Both patients underwent intraoperative repair with onlay autologous tissue graft followed by dural sealant after discectomy was completed without evidence of pseudomeningocele, but they developed postoperative positional headaches and presumed IH. Both patients received an early EBP with an immediate and complete resolution of positional headaches sparing them reoperation and/or lumbar drainage. EBP should be considered as a first-line treatment to treat postoperative IH symptoms without pseudomeningocele after iatrogenic CSF leak during tubular microdiscectomy.

Validation of corpus callosotomy after laser interstitial thermal therapy: a multimodal approach.

ObjectiveDisconnection of the cerebral hemispheres by corpus callosotomy (CC) is an established means to palliate refractory generalized epilepsy. Laser interstitial thermal therapy (LITT) is gaining acceptance as a minimally invasive approach to treating epilepsy, but this method has not been evaluated in clinical series using established methodologies to assess connectivity. The goal in this study was to demonstrate the safety and feasibility of MRI-guided LITT for CC and to assess disconnection by using electrophysiology- and imaging-based methods.MethodsRetrospective chart and imaging review was performed in 5 patients undergoing LITT callosotomy at a single center. Diffusion tensor imaging and resting functional MRI were performed in all patients to assess anatomical and functional connectivity. In 3 patients undergoing simultaneous intracranial electroencephalography monitoring, corticocortical evoked potentials and resting electrocorticography were used to assess electrophysiological correlates.ResultsAll patients had generalized or multifocal seizure onsets. Three patients with preoperative evidence for possible lateralization underwent stereoelectroencephalography depth electrode implantation during the perioperative period. LITT ablation of the anterior corpus callosum was completed in a single procedure in 4 patients. One complication involving misplaced devices required a second procedure. Adequacy of the anterior callosotomy was confirmed using contrast-enhanced MRI and diffusion tensor imaging. Resting functional MRI, corticocortical evoked potentials, and resting electrocorticography demonstrated functional disconnection of the hemispheres. Postcallosotomy monitoring revealed lateralization of the seizures in all 3 patients with preoperatively suspected occult lateralization. Four of 5 patients experienced > 80% reduction in generalized seizure frequency. Two patients undergoing subsequent focal resection are free of clinical seizures at 2 years. One patient developed a 9-mm intraparenchymal hematoma at the site of entry and continued to have seizures after the procedure.ConclusionsMRI-guided LITT provides an effective minimally invasive alternative method for CC in the treatment of seizures associated with drop attacks, bilaterally synchronous onset, and rapid secondary generalization. The disconnection is confirmed using anatomical and functional neuroimaging and electrophysiological measures.

Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity.

Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state. Combination therapy reduced the frequency of these subsets, while simultaneously inducing a separate polyfunctional inflammatory TAM subset cosecreting TNF-α, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-α and IFN-γ. Together, this study demonstrates the potential for targeting TAMs to convert a "cold" into an "inflamed" tumor microenvironment capable of eliciting protective T cell responses.

A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers.

The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a "dormant" TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer.

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.

Ventriculoperitoneal Shunt Infection with Mycobacterium abscessus: A Rare Cause of Ventriculitis.

BACKGROUND: Mycobacterium abscessus is a rapidly growing atypical mycobacterium implicated in chronic lung disease, otitis media, surgical site infections, and disseminated cutaneous diseases. It is typically seen in patients with some degree of immunosuppression. Only 1 previous case has been reported in the setting of ventriculoperitoneal (VP) shunt infection. We report a case of M abscessus as the causative organism in a VP shunt infection in an immunocompetent adult. CASE DESCRIPTION: A 67-year-old woman required VP shunt placement after aneurysmal subarachnoid hemorrhage complicated by hydrocephalus. Her course was complicated by repeat hospitalization for 2 shunt infections, the second of which did not respond to standard antibiotic therapy. Cultures repeatedly grew M abscessus. The patient continued to decline and eventually died after transfer to the palliative care service. CONCLUSIONS: Nontuberculous mycobacteria are rare, atypical organisms in the setting of VP shunt infection. Patients with ventriculitis secondary to atypical mycobacteria may exhibit drug-resistant cerebrospinal fluid pleocytosis in the face of standard antibiotic regimens.

Brief Report: Enhanced Allogeneic Cellular Responses to Mismatched HLA-B Antigens Results in More Efficient Killing of HIV Infected Cells.

Epidemiologic studies have demonstrated that HIV-1 discordant couples who share HLA-B alleles were more likely to transmit HIV-1. These data lead us to hypothesize that individuals who match at both HLA-B alleles should have a reduced allogeneic response than those who are not matched. We observed diminished killing of CD4 target cells only when HLA-B alleles were matched. We propose that for cell-associated HIV-1 transmission, the ability of the recipient to eliminate infected cells from a donor partner may be enhanced when HLA-B alleles are different between partners. These findings suggest a novel mechanism for protection against HIV infection.

Impact of pre-adapted HIV transmission.

Human leukocyte antigen class I (HLA)-restricted CD8(+) T lymphocyte (CTL) responses are crucial to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, as these variants can also reduce intrinsic viral fitness. To address this, we here developed a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses that are pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4(+) T cell decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to the expression of certain HLA alleles. Thus, viral pre-adaptation exploits 'holes' in the immune response. Accounting for these holes may be key for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies that require broad CTL responses to achieve successful eradication of HIV reservoirs.