Why is there expanding community transmission of monkeypox in 2022?

In The Lancet Microbe, Akaninyene Otu and colleagues¹ called for urgent public health action for the 2022 monkeypox outbreak, noting that cases outside of Africa since May 7, 2022, have exceeded the overall number of cases detected outside of endemic areas from 1970 to the current outbreak. The newest rate of human infections is even more alarming when we consider that cases in the last 2 months vastly exceeded the number of confirmed or suspected human monkeypox cases in the entire 20th century.²

Sequencing by Isidro and colleagues revealed that the circulating monkeypox virus descended from a clade sampled in cases in Nigeria, Singapore, Israel, and the UK between 2017 and 2019.³ Happi and colleagues described a new clade system and gave the circulating virus the provisional name human monkeypox virus 1 (hMPXV1).⁴ Furthermore, Nextstrain's molecular clock analysis of hMPXV1 shows extensive diversity in the descendant lineages A.1, A.2, A.1.1, and B.1.

O'Toole and Rambaut observed that a cytidine deaminase called apolipoprotein B editing complex (APOBEC3) could be driving the recent rapid evolution of hMPXV1.⁴ Cytidine deaminases alter DNA, leading to double-stranded breaks at switch regions. In human cells, a cytidine deaminase known as activation-induced cytidine deaminase drives somatic mutations crucial for producing new antibodies. APOBEC3 proteins are essential for retroviruses and play important roles in single-strand DNA regulation of DNA viruses such as parvovirus, hepatitis B, and herpes viruses.

Although it is helpful to know what is driving the mutational changes, it is equally crucial to understand how genetic alterations are facilitating human-to-human transmission. By understanding how changes alter functions, this might help predict potential problems with existing medical countermeasures and will facilitate the production of new antiviral tools. Knowing which molecules function differently will allow us to target those molecules with appropriate countermeasures. Detecting changes in the function of monkeypox proteins known to alter pathogenesis would allow us to target those molecules to decrease disease and possibly transmission. The panel provides an overview of suggested future studies to identify how mutational changes in hMPXV1 could alter viral pathogenesis in humans. These studies could provide excellent clues for tools that can help halt the spread of monkeypox in humans.

Panel. Suggested future studies to establish how mutational changes in hMPXV1 might provide an advantage in a human host.

Improved entry into human cells (speed, quality, and variety of entry mechanisms)

Improved viral replication

• •Enhanced use of host machinery for viral replication (eg, more compatible use of codons, better use of energy from host cells such as the use of lipids)
• •Enhanced avoidance of catabolic mechanisms within the host cell
• •Altered tolerance to microenvironmental changes in pH, temperature, or ion concentrations

Improved exocytosis

• •Enhanced packaging for exit from cells
• •Cell lysis better coordinated with the optimal release of formed mature virions
• •Alteration in proportions of mature virions that become wrapped virions and then exit as enveloped virions
• •Release of molecules that reorganise cytoskeletal elements and their functions

Improved evasion of innate defences mechanisms

• •Inhibitors of cellular or soluble pattern recognition receptors, or decoy molecules that alter pattern recognition receptors or their functions
• •Release of molecules that alter the functions of substances released from granules such as chemokines, kinins, or eicosanoids

Improved evasion of adaptive defence mechanisms

• •Decoy molecules
• •Altered viral molecules that evade existing B-cell receptors or antibodies and T-cell receptors
• •Molecules that alter the function of cytokines and chemokines

Improved stability outside of a host

• •Factors that reduce decay of DNA (eg, increased tolerance to changes in pH, humidity, or temperature)

I declare no competing interests.