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Summary Background In 2019, WHO reported that the prevalence of HIV-1 drug resistance to first-line regimens of non-nucleoside 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. Findings The 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 potential to affect patient management. Funding None.

[Background] Several host factors contribute to human immunodeficiency virus (HIV) disease progression in the absence of combination antiretroviral therapy (cART). Among them, the CC-chemokine receptor 5 (CCR5) is known to be the main co-receptor used by HIV-1 to enter target cells during the early stages of an HIV-1 infection., [Objective] We evaluated the association of CCR5(WT/Δ32) heterozygosity with HIV-1 reservoir size, lymphocyte differentiation, activation and immunosenescence in adolescents and young adults with perinatally acquired HIV infection receiving cART. [Methods] CCR5 genotype was analysed in 242 patients with vertically transmitted HIV-1 infection from Paediatric Spanish AIDS Research Network Cohort (coRISpe). Proviral HIV-1 DNA was quantified by digital-droplet PCR, and T-cell phenotype was evaluated by flow cytometry in a subset of 24 patients (ten with CCR5(Δ32/WT) genotype and 14 with CCR5(WT/WT) genotype). [Results] Twenty-three patients were heterozygous for the Δ32 genotype but none was homozygous for the mutated CCR5 allele. We observed no difference in the HIV-1 reservoir size (455 and 578 copies of HIV-1 DNA per million CD4+ T cells in individuals with CCR5(WT/WT) and CCR5(Δ32/WT) genotypes, respectively; p 0.75) or in the immune activation markers between both genotype groups. However, we found that total HIV-1 DNA in CD4+ T cells correlated with the percentage of memory CD4+ T cells: a direct correlation in CCR5(WT/Δ32) patients but an inverse correlation in those with the CCR5(WT/WT) genotype. [Conclusions] This finding suggests a differential distribution of the viral reservoir compartment in CCR5(WT/Δ32) patients with perinatal HIV infection, which is a characteristic that may affect the design of strategies for reservoir elimination., We particularly acknowledge the Spanish HIV HGM BioBank supported by the Spanish Instituto de Salud Carlos III, which is integrated with the Spanish AIDS Research Network. We thank V. Urrea (AIDS Research Institute IrsiCaixa, Badalona) for statistical support. IrsiCaixa is supported by the CERCA programme from Generalitat de Catalunya. Work by the group of MAMF was supported by Instituto de Salud Carlos III (Subdirección General de Evaluación) and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT13/0010/0028, Fondo de Investigacion Sanitaria (FIS) (grants PI13/02016, PI12/0014 and CD14/00320 to AGS), Comunidad de Madrid (grant S-2010/BMD-2332]. This work was (partially) funded by the RD12/0017/0037 project as part of the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008–2011 (HGUGM) and by CYTED 214RT0482. CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. This project was also supported by the Spanish Secretariat of Research (grant Red Temática de Investigación Cooperativa en SIDA [RD12/0017] and CPII014/00025 and PI12/02283 from Fondo de Investigación Sanitaria (FIS) to E.R.-M.) Work by the JM-P group is supported by the Spanish Secretariat of Research (grant SAF2013-49042-R), the Foundation for AIDS Research (amfAR), and the Spanish AIDS network ‘Red Temática Cooperativa de Investigación en SIDA’ (RD12/0017/0002). S.M-L. was supported by Agència de Gestió d’Ajuts Universitaris i de Recerca from Generalitat de Catalunya (2013FI_B 00275).

Deletions in the beta 3-beta 4 hairpin loop of human immunodeficiency virus type 1 reverse transcriptase (RT) are associated with the emergence of multidrug resistance. Common mutational patterns involve the deletion of Asp67 (Delta 67) and mutations such as K70R and T215F or T215Y, or the deletion of Thr69 (Delta 69) and mutations of the Q151M complex. Human immunodeficiency virus type 1 clones containing Delta 69 in a multidrug-resistant sequence background, including the Q151M complex and substitutions K103N, Y181C, M184V, and G190A, showed high-level resistance to all tested nucleoside RT inhibitors. In a multidrug-resistant sequence context, the deletion increases viral replication capacity. By itself, Delta 69 conferred increased susceptibility to beta-d-(+)-3'-azido-3'-deoxythymidine (AZT) and beta-l-(-)-2',3'-dideoxy-3'-thiacytidine resistance. Here, we use transient kinetics to show that, in a wild-type sequence background, Delta 69 does not affect the discrimination between AZT triphosphate and 2'-deoxythymidine 5'-triphosphate, but decreases the catalytic efficiency of the incorporation of beta-l-(-)-2',3'-dideoxy-3'-thiacytidine triphosphate relative to 2'-deoxycytidine 5'-triphosphate. In comparison with the wild-type RT, the Delta 69 mutant showed decreased ability to excise primers terminated with AZT monophosphate in the presence of ATP or pyrophosphate (PPi). These data support the role of the excision mechanism in mediating AZT hypersusceptibility. In addition, we demonstrate that the deletion has no effect on resistance to foscarnet (a PPi analogue) on phenotypic and nucleotide incorporation assays carried out with viral clones and recombinant enzymes, respectively. The results of molecular modeling studies suggest that the side chains of Lys65, Asp67, and Lys219 could play an important role in AZT hypersusceptibility mediated by Delta 69, whereas in the absence of Thr69, local structural rearrangements affecting the beta 3-beta 4 and beta 11a-beta 12 loops of the 66-kDa subunit of the RT could reduce the accessibility of the PPi donor to the terminating nucleotide at the 3' end of the primer.