Despite advances in antiretroviral therapy that have revolutionized HIV disease management, effective control of the HIV infection pandemic remains elusive. Beyond the classic non-B endemic areas, HIV-1 non-B subtype infections are sharply increasing in previous subtype B homogeneous areas such as Europe and North America. As already known, several studies have shown that, among non-B subtypes, subtypes C and D were found to be more aggressive in terms of disease progression. Luckily, the response to antiretrovirals against HIV-1 seems to be similar among different subtypes, but these results are mainly based on small or poorly designed studies. On the other hand, differences in rates of acquisition of resistance among non-B subtypes are already being observed. This different propensity, beyond the type of treatment regimens used, as well as access to viral load testing in non-B endemic areas seems to be due to HIV-1 clade specific peculiarities. Indeed, some non-B subtypes are proved to be more prone to develop resistance compared to B subtype. This phenomenon can be related to the presence of subtype-specific polymorphisms, different codon usage, and/or subtype-specific RNA templates. This review aims to provide a complete picture of HIV-1 genetic diversity and its implications for HIV-1 disease spread, effectiveness of therapies, and drug resistance development. 1. Introduction Thirty years have passed after discovering human immunodeficiency virus (HIV), the etiological agent of the acquired immunodeficiency syndrome (AIDS) [1–4]. Two types of HIV are known: the most common HIV-1, which is responsible to the worldwide AIDS epidemic, and the immunologically distinct HIV-2 [5], which is much less common and less virulent [6, 7] but produces clinical findings similar to HIV-1 [8]. The HIV-1 type itself includes four groups M (main), O (outlier), N (non-M, non-O), and P [9–12], which have different geographic distributions but all produce similar clinical symptoms. The M group further splits into 9 subtypes (A through J) [13–15], as well as at least 58 circulating recombinant forms (CRFs, http://www.hiv.lanl.gov/content/sequence/HIV/CRFs/CRFs.html, last accessed 06 May 2013) and multiple unique recombinant forms (URFs). The vast majority of reports on drug resistance deal with HIV-1 subtype B infections in developed countries, and this is largely due to historical delays in access to antiretroviral therapy on a worldwide basis. Advances in antiretroviral therapy have revolutionized HIV management and the control of the spread of regional epidemics
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