Rare but relevant: a comprehensive narrative review of rare HIV-1 group M subtypes

Human immunodeficiency virus type 1 (HIV-1) group M comprises 10 genetically diverse subtypes, with subtypes C and B being the most prevalent globally. However, rare subtypes F, H, J, K, and L, though individually responsible for less than 1% of HIV-1 infections worldwide, play relevant roles in viral evolution, global persistence, recombination, and drug resistance. This review provides a comprehensive synthesis of the available literature on these rare subtypes for the first time, emphasizing their distribution, recombination patterns, transmission dynamics, and drug resistance-associated mutations. A key observation is that many of these rare subtypes are more frequently found in recombinant forms than in non-recombinant forms, which may expand their geographic distribution and sustain their epidemiological presence. We further highlight drug resistance-associated mutations in the protease and reverse transcriptase regions of the rare subtypes, which may affect treatment outcomes. Advances in molecular tools, such as next-generation sequencing and Bayesian phylogeographic analyses, have improved the identification of the rare subtypes in both recombinant and non-recombinant forms. However, there remains a significant data gap in the clinical impact of these subtypes as they continue to be undersampled and understudied. This review thus underscores the need for augmenting subtype-specific surveillance strategies, especially in regions where the rare subtypes predominantly circulate. Expanding research on these rare subtypes will be essential for understanding HIV-1 recombination and evolutionary dynamics, identifying trends in drug resistance, and developing more globally inclusive anti-viral strategies that better reflect the diversity of HIV-1.