Genetic and phylogenetic evolution of HIV-1 in a low subtype heterogeneity epidemic: the Italian example
© Buonaguro et al; licensee BioMed Central Ltd. 2007
Received: 09 February 2007
Accepted: 21 May 2007
Published: 21 May 2007
The Human Immunodeficiency Virus type 1 (HIV-1) is classified into genetic groups, subtypes and sub-subtypes which show a specific geographic distribution pattern. The HIV-1 epidemic in Italy, as in most of the Western Countries, has traditionally affected the Intra-venous drug user (IDU) and Homosexual (Homo) risk groups and has been sustained by the genetic B subtype. In the last years, however, the HIV-1 transmission rate among heterosexuals has dramatically increased, becoming the prevalent transmission route. In fact, while the traditional risk groups have high levels of knowledge and avoid high-risk practices, the heterosexuals do not sufficiently perceive the risk of HIV-1 infection. This misperception, linked to the growing number of immigrants from non-Western Countries, where non-B clades and circulating recombinant forms (CRFs) are prevalent, is progressively introducing HIV-1 variants of non-B subtype in the Italian epidemic. This is in agreement with reports from other Western European Countries.
In this context, the Italian HIV-1 epidemic is still characterized by low subtype heterogeneity and represents a paradigmatic example of the European situation. The continuous molecular evolution of the B subtype HIV-1 isolates, characteristic of a long-lasting epidemic, together with the introduction of new subtypes as well as recombinant forms may have significant implications for diagnostic, treatment, and vaccine development. The study and monitoring of the genetic evolution of the HIV-1 represent, therefore, an essential strategy for controlling the local as well as global HIV-1 epidemic and for developing efficient preventive and therapeutic strategies.
HIV-1 genetic subtypes
HIV-1 phylogenetic classifications are currently based either on nucleotide sequences derived from multiple sub genomic regions (gag, pol and env) of the same isolates or on full-length genome sequence analysis. This approach has revealed virus isolates in which phylogenetic relations with different subtypes switch along their genomes. These inter-subtype recombinant forms are thought to have originated in individuals multiply infected with viruses of two or more subtypes. This results in the generation of several recombinants called "unique recombinant forms," or URFs . When an identical recombinant virus is identified in at least three epidemiologically unlinked people, and is characterized by full-length genome sequencing, it can be designated as circulating recombinant forms (CRFs) [5–7]. The intra-genomic recombination appears to be a very frequent event and the CRFs account for 18% of incident infections in the global HIV-1 pandemic [8, 9].
HIV-1 epidemic in Italy
More than 10% of heterosexual individuals diagnosed with AIDS in Italy are either immigrants from endemic regions for HIV-1 (6.87%) or their Italian partners (3.03%). This epidemiological evidence, not considering all the HIV-1 infections derived also from traveling abroad, suggests that at least 10% of the viruses transmitted through heterosexual contacts could potentially belong to non-B subtypes and CRFs. This has been recently reported in other European Countries, with a higher prevalence due to an older tradition of immigration waves and much tighter historical as well as economic links with countries endemic for HIV-1 infection [14–22]
Molecular evolution of the B-clade envsequences in the Italian epidemic
The biological relevance of genetic variations in the env gene is due to the central role of the envelope protein in the virus-host interaction. In particular, the V3 loop contains epitopes for strain-restricted neutralizing antibodies, it is a major determinant for viral tropism and co-receptor usage, and its orientation partially masks the CD4 and chemokine receptor binding sites [23–31].
The analysis performed including the B-subtype Italian sequences [32–45] has shown a progressive increase of nucleotide divergence in this region, increasing from 9.2% between isolates identified in the late 80's , to 17.51% between isolates identified in the early 2000's [33, 45]. This closely resembles the expected evolution of a region under a strong immunological pressure during a long-lasting epidemic [45, 47].
Rate of amino acid substitution and codon usage in the B-clade V3 envsequences
Furthermore, amino acid substitutions in the V3 loop show a significant uniform distribution in the HIV-1 sequences identified during the Italian epidemic, with the exception of the T-to-A22 substitution (within the tip of the loop) which is prevalent in the isolates identified in the early 2000's.
Non-B-clade envsequences in Italian epidemic
So far, during the entire HIV-1 epidemic in Italy, only seven non-B clade env sequences have been described, identified in heterosexual individuals (either immigrants from sub-Saharan Africa or their Italian partners) [44, 45]; [33, 34]. In particular, a very recent near-full length sequence analysis has shown that a HIV-1 isolate originally classified as A is actually close to the A3 sub-subtype and does not cluster in any of the known subtypes. It could potentially represents a novel sub-subtype, which needs to be confirmed with the identification of at least two additional related isolates in unlinked individuals .
Molecular evolution of the B-clade proteasesequences in Italian epidemic
The sequences relative to HIV-1 pol gene, and the protease region in particular, have been extensively analyzed and collected only from the year 2000, consequent to appearance of viral isolates resistant to protease inhibitors (PI), introduced as a component of anti-retroviral therapy (ART) combinations. This effect has made obvious the need to evaluate the resistant mutants to guide the choice of drug combinations in heavily drug-treated HIV-1-infected individuals as well as in recent treatment-naïve seropositive individuals.
The nucleotide divergence of the protease region during the HIV-1 epidemic in Italy has been evaluated including all the B-subtype Italian sequences from the published reports [53–64]. The analysis, unlike the analyses of the V3 env region, has shown a rather constant nucleotide divergence in this region (6.83% – 7.68%) over the 2000–2006 period. These results confirm that, also in a long-lasting epidemic, the pol genes (and the protease in particular) are not driven to genetic change by immunologic pressure.
The phylogenetic analyses, therefore, strongly suggest that, as for the env region, the protease region of the pol gene in HIV-1 B subtypes in Italy are derived from three main molecular ancestors, which have continuously evolved and spread among infected individuals during the epidemic.
Non-B-clade proteasesequences in Italian epidemic
Gagsequences in Italian epidemic
The B clade remains predominant and is circulating among all risk groups in the Italian epidemic, as observed all across Western European Countries . Nevertheless, the structural genes of B subtype HIV-1 variants show a continuous spectrum of genetic diversification, although the currently circulating viruses appear to derive from a few early "founders". The introduction and the spread of non-B subtype HIV-1 isolates in the Italian epidemic, in contrast, appear to be still limited. In particular, as reported in other Western European countries, it is strongly associated with heterosexual transmission between local and immigrant/migrant partners. In this regard, it has to be mentioned that the general strategy of sequencing and performing phylogenetic analyses only on the env sub-genomic region, pursued in Italy and worldwide for many years, could have resulted in missing the identification of novel CRFs early in the Italian epidemic.
The Italian HIV-1 epidemic, therefore, represents a paradigmatic example of the European situation, being still characterized by low subtype heterogeneity. However, the slow introduction and diffusion of non-B subtypes in the population could progressively change the overall scenario and drive the need of adapting the diagnostic and treatment strategies currently used in European Countries.
This study was supported by grants from the Ministero Italiano della Sanità (Ricerca Corrente and Progetto Finalizzato AIDS 2002) and the ICSC-World Lab, Lausanne, Switzerland (Project MCD-2/7). We are grateful to Marv Reitz (Inst. Human Virol., Baltimore – MD) for his critical reading of the manuscript. MT is a Ph.D. student in "Experimental Medicine and Oncology" Program, at the Univ. of Insubria – Varese, Italy.
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