Unusual Monkeypox virus outbreak in 2022: Phenotypic and molecular characteristics

Monkeypox virus, first identified in 1958 in Asian monkeys employed for experiments in a laboratory in Denmark and then in 1970 in humans in Africa, in the Democratic Republic of Congo (DRC), has continued to circulate for about 50 years in some regions of Africa, indicated as Congo Basin (CB) and West Africa (WA) where it has become endemic. Rare outbreaks have occurred outside endemic countries, linked to importation of the virus from endemic areas. Suddenly, since early May 2022, cases of MPX developed outside the endemic areas and their number increased rapidly. Important differences in the epidemiology of 2022 MPX compared to previous MPX spread have begun to be observed soon. First, the 2022 cases could not be traced to contacts with infected cases or animals from endemic countries. The 2022 cases are due to human-to-human transmission and not to contact with infected animals; among the transmission routes the sexual route seems to predominate, particularly among men who have sex with men (MSM). Affected countries are located on several continents, mainly in America and Europe, but also in Asia and Australia. As of mid-November 2022, 110 countries have reported MPX cases, for a total of more than 79,000 confirmed cases and 50 deaths. What is behind this new MPXV behavior and what consequences might it have? This review aims to clarify the possible underpinnings of this 2022 MPX outbreak, with a focus on the molecular mechanisms, through an analysis of the literature. Most of the studies undertaken for this purpose are concerned with the molecular genetics of MPXVs and have been based on analysis and sequence comparison of the different species of the OPXV genus, of isolates of the two different MPXV Clades, of MPXVs in circulation before and during 2022, as well as of MPXVs identified from May 2022 onwards. These studies, reveal some variations mainly in the sequences of the Inverted Terminal Repeats (ITRs), known, on the other hand, as more variable regions of the viral genome. These are variations mainly in the genes involved in the virus-host relationship, virulence and immune evasion. However, further studies are needed to confirm the real significance of these variations in virus evolution. Of particular interest is the observation, shared by many authors, of the frequency of mutations in the MPXVs 2022 genome associated with APOBEC activity. These mutations may in fact represent a marker of human-to-human transmission that characterizes the new MPXV isolates. Overall, the variability of the MPXVs 2022, grouped in the B.1 lineage of Clade IIb, is not particularly high compared, for example, to many RNA viruses. However, it is still much higher than that of the previously circulated MPXV. Even if the epidemiological curve has changed trend in the past 3 months, it remains important to shed full light on the causes the multinational MPX outbreak of 2022.