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.

NCT01400412.

We identified the concurrent expansion of multiple small transmission clusters rather than a single outbreak in a largely disconnected contact tracing network. Integration of phylogenetic analyses provided timely information on transmission networks during the investigation. Our findings highlight the potential of combined methods to better identify high-risk networks for intervention.

Background In 2019, WHO reported that the prevalence of HIV-1 drug resistance to first-line regimens of nonnucleoside reverse transcriptase inhibitors is increasing in countries with a low number of therapeutic options. This increasing prevalence of drug resistance is an important threat to ending the AIDS pandemic, as it compromises individual clinical outcomes and increases the risk of transmission. In countries with a high number of therapeutic options, little global information is available regarding the prevalence of multidrug-resistant HIV-1 infections, which presents a potential challenge for the clinical management of people with HIV. Even after the approval of two new antiretroviral drug classes in 2007, which were intended to help alleviate this problem, some cases of infection with HIV-1 that show limited susceptibility to the five available antiretroviral classes have been described. We did a thorough in-vitro evaluation of the drug resistance profile of HIV-1 from an observational case to show that five-class pan-resistant clinical cases do exist.Methods We investigated a case of a highly treatment-experienced Caucasian male with HIV-1 who had a poor virological response to previous combination antiretroviral therapy (ART) and who was not responding to a dolutegravir-based regimen. For the complete panel of approved antiretrovirals, we examined genotypic resistance using the Stanford HIV Drug Resistance Database interpretation algorithm, and we examined phenotypic resistance using the PhenoSense and Trofile assays. Using viral gp160 sequence analysis, we also explored the potential susceptibility of this virus to novel therapeutic drugs targeting viral envelope binding. FindingsThe individual was diagnosed with HIV-1 on Sept 29, 1989. Since starting antiretroviral treatment in 1995, the individual had received more than 14 different antiretroviral drugs over the course of his illness. In November, 2017, a blood sample was collected from the individual and we did drug resistance analysis tests. We found that this individual was infected with a pan-resistant HIV-1 subtype B strain that showed broad genotypic and phenotypic cross-resistance to all approved antiretroviral drugs, including the newest second-generation integrase inhibitors, dolutegravir and bictegravir. With no remaining clinical options available, except for investigational drugs, this case provides evidence that new antiretroviral drugs with different mechanisms of action are needed.Interpretation Our case report shows that HIV-1 multidrug cross-resistance remains an important concern, despite the extensive number of antiretroviral drugs currently available. Highly treatment-experienced patients, especially those who have been given suboptimal combination ART, can develop highly complex resistance-associated mutation patterns, conferring cross-resistance to all widely available ARTs. The identification and reporting of cases, such as the one described in this report, are needed to increase awareness of emerging trends that have the poten...

Transmitted HIV-1 exhibiting reduced susceptibility to protease and reverse transcriptase inhibitors is well documented but limited for integrase inhibitors and enfuvirtide. We describe here a case of transmitted 5 drug class-resistance in an antiretroviral (ARV)-naïve patient who was successfully treated based on the optimized selection of an active ARV drug regimen. The value of baseline resistance testing to determine an optimal ARV treatment regimen is highlighted in this case report.