We've updated our Privacy Policy to make it clearer how we use your personal data. We use cookies to provide you with a better experience. You can read our Cookie Policy here.


Viral Evolution: Changing Priorities Under Environmental Cues

Human immunodeficiency virus-1 virions in the process of budding from a cultured lymphocyte.
Scanning electron microscopic (SEM) image of human immunodeficiency virus-1 (HIV-1) virions seen as small round bumps, in the process of budding from a cultured lymphocyte. Credit: C. Goldsmith/ CDC
Listen with
Register for free to listen to this article
Thank you. Listen to this article using the player above.

Want to listen to this article for FREE?

Complete the form below to unlock access to ALL audio articles.

Read time: 8 minutes

Human host–virus co-evolution has been occurring for hundreds of thousands of years, since the dawn of modern humans. The evidence of human viral infection is even imprinted in our DNA, where, for example, remnants of retroviruses from previous infection can be observed. Today, host–virus evolution continues, shaped and molded by environmental cues that apply selective pressures on the mutating virus, favoring the variants that are the most fit to survive in the shifting landscape. Sometimes, mutations that help a virus survive some situations, e.g., within a host during chronic infection, exact a toll on fitness under different circumstances, e.g., between host transmission. Thus, changing host conditions dictate viral evolution.

This article will describe this everchanging scenario for two viruses, human parainfluenza virus (HPIV) and human immunodeficiency virus (HIV), to highlight some of the selective pressures on rapidly mutating viruses.

Human parainfluenza virus (HPIV): A significant respiratory virus

HPIVs are enveloped, single-stranded RNA viruses belonging to the Paramyxoviridae family. There are three HPIVs, 1, 2 and 3, the last accounting for most infections. Of the children under 5 years old hospitalized for fever and/or serious respiratory infection in the United States, 4 to 14% have been attributed to HPIV infection. It is also a significant respiratory virus in immunocompromised patients, such as transplant recipients and older individuals.

“Currently, we don’t have effective vaccines or therapeutics against HPIVs,” explained Anne Moscona, professor and director of the Center for Host–Pathogen Interaction at Columbia University Department of Pediatrics. Moscona investigates the impact of the environment, or host setting, on HPIV viral evolution and fitness. “The single-stranded RNA genome of HPIV3 tends to mutate rapidly because its polymerase lacks a repair function. Thus, HPIV3 adapts to its host, be it a human in vivo or culture in vitro,” Moscona elaborated of the virus’s dynamics.

HPIV entry into host cells: It takes two to tango

HPIV viruses enter host cells via the concerted effort of two viral surface glycoproteins, the receptor-binding protein hemagglutinin-neuraminidase (HN) and fusion (F) protein. “HN has four roles. First, it stabilizes pre-fusion F, preventing premature activation. Second, HN mediates binding to host receptors that display α2–3 or α2–6-linked terminal sialic acids; the strength of this interaction is called avidity. Third, once engaged to the host receptor, HN triggers F, meaning it induces structural changes to F, causing it to pierce and initiate fusion with the host membrane. Lastly, HN cleaves the receptor, disengaging from it. As you can see, it is a tightly orchestrated process,” described Moscona.

Given the closely regulated nature of the interaction between HN and F, mutations at key residues introduced during viral replication alter host entry dynamics. Specific mutations will be advantageous, disadvantageous or neutral to the virus, depending on the host conditions. “HPIV3 variants that are fit, i.e., have advantageous mutations, in vivo during acute infection have lower HN avidity for host receptors, which allows the virus to attain the lower respiratory tract and deeper lung tissues before attempting to infect. Fit variants also ensure HN does not prematurely trigger F, otherwise the virus will “activate” before it contacts with host cells, meaning F protein will not pierce the host membrane nor initiate fusion and the trigger will have been wasted,” elaborated Moscona.

“In contrast, in vitro, the virus immediately contacts with cells in culture, so premature activation is not a concern. In this scenario of persistent infection, higher HN avidity for the host receptor and enhanced F triggering become an advantage, which promotes cell-to-cell spread. Thus, the host conditions dictate viral evolution. Mutations that are normally disadvantageous during acute infection in vivo in a human can become advantageous in vitro in persistently infected culture.”

HPIV in immunocompromised hosts: A persistent scenario in vivo

A different scenario arises in immunocompromised patients versus patients who clear an acute infection. An immunocompromised host does not quickly or properly clear HPIV3 due to impaired immunity, which permits the virus longer residency in the lung and the opportunity to establish a persistent infection. “During its extended time in the lung, the virus evolves, and the same principles of fitness apply. Advantageous mutations flourish,” explained Moscona. To identify the advantageous mutations, Moscona and her team, in collaboration with Alex Greninger at the University of Washington, examined HPIV3 evolution in two immunocompromised patients by sequencing the virus from patient nasal swabs or bronchoalveolar lavage. Mutations consistent with higher HN host receptor avidity and enhanced F triggering emerged.

“Mutations that favored persistent infection in vivo in an immunocompromised host mirrored mutations that helped the virus spread in vitro in culture, namely the H552Q mutation in HN, which we identified in an earlier study. Given time to evolve in the lung, the virus gained mutations that helped it survive within the host by spreading cell-to-cell, as it does in culture. This contrasts with mutations that would instead help HPIV3 transmit from host-to-host, such as lower HN host receptor avidity and more controlled F triggering, which is needed to allow virions to traverse the respiratory tract without activating,” elaborated Moscona.

It should be noted that one of the two study participants also received DAS181 treatment, a sialic acid cleaving drug that strips host cells of their sialic acids, which is under investigation as a human therapeutic for lower respiratory tract parainfluenza infection in immunocompromised patients. Treating cultures in vitro with DAS181 has been found to favor the emergence of the fusion-promoting H552Q mutation in HN. So, the selective pressures that elicited the H552Q mutation to HN in vitro in culture have effectively been replicated in the host. Despite the small numbers and confounding factors in this study, the emergence of the same mutations in immunocompromised hosts and in culture, i.e., H552Q mutation to HN, is interesting and raises important therapeutic considerations. “It is suggestive that persistent infection in the lung may also promote HPIV3 HN’s H552Q mutation. This is a correlative finding and further study is needed, but it does raise concerns about this form of host-directed DAS181 therapy, and I would suggest closely monitoring immunocompromised patients treated with this drug for the emergence of fusion-promoting mutations,” explained Moscona.

Moscona further added that it is important to consider that viruses rapidly and deftly adapt to their environment, evolving to fit the host setting. So, if the host setting changes, so too will the virus, evolving to survive that change. “Host-directed therapeutics – be it DAS181 that cleaves sialic acids from the host, or other therapeutics that alter host receptor molecules, membranes or innate immune pathways – will all provide a selective pressure for the virus to evolve!” Moscona concluded. “Viral evolution under selective pressures is of particular concern in immune compromised patients with long-term persistent infections, at least for this group of paramyxoviruses. Treating persistently infecting viruses will require a strategy that prevents cell-to-cell virus spread once infection has been established. It may also be that antivirals that directly target the virus, as opposed to those that target the host, may be advantageous.”

Human immunodeficiency virus (HIV): A continued health threat

HIV is an enveloped, single-stranded RNA virus belonging to the Retroviridae family. Once the virus penetrates a host cell, its RNA genome is reverse transcribed into double-stranded DNA, which integrates into the host genome. HIV is subdivided into two types, HIV-1 and HIV-2, the former leading to more progressive illness. Nevertheless, both HIV types contribute substantially to the global burden of disease and are responsible for acquired immunodeficiency syndrome (AIDS). Despite significant advances in managing infection and transmission, there were 38.4 million people living with HIV worldwide in 2021, along with 1.5 million new cases and 650,000 AIDS-related deaths. Among people living with HIV, 28.7 million had access to antiretroviral therapy (ART).

“ART has vastly improved quality-of-life and survival prospects for people with HIV,” explained Ana B. Abecasis, professor of Global Health and Tropical Medicine at the Institute for Hygiene and Tropical Medicine, University Nova de Lisboa, Portugal. “Widespread ART use has also reduced the risk of HIV transmission in communities, which has led to a decline in HIV infection rates. Unfortunately, despite progress, obstacles remain to eradicating the virus, due to, among many other reasons, the development of drug resistance among HIV strains, which mutate rapidly.”

HIV yin and yang: Within-host evolution and between-host transmission

To eradicate HIV, it is essential to understand the dynamics of within-host viral evolution versus between-host viral transmission, in order to implement appropriate strategies. “Within-host HIV-1 evolution is dictated by selective pressure, for example, from host immune responses or ART. Random mutations may confer an advantage to HIV-1, for example by helping it evade the host immune system or circumvent ART inhibitors, e.g., protease inhibitors, which allow the virus to establish a chronic infection. At the same time, mutations that are favorable under certain selection pressures may incur costs, such as impaired replication, which would lead to lower viral load and potentially reduced transmissibility,” Abecasis elaborated.

Although between-host transmission was previously thought to occur mostly by chance, studies increasingly suggest that selective pressures also operate. “The contribution of selective pressure on viral transmission is supported by multiple lines of evidence,” Abecasis outlined. “First, several studies have shown that certain HIV-1 strains favorably spread between hosts. Infectiousness is especially higher in HIV-1 variants that more closely resemble ancestral strains, which suggests that contemporary, highly evolved strains within the host can be less fit for transmission. Second, specific structural characteristics in viral envelope proteins may predispose to transmission, again indicative of selective pressure on host-to-host spread.” Thus, between-host HIV-1 transmission may be determined by both stochastic and selective pressures.

Overall, within-host HIV-1 evolution is a balancing act against virus transmission. Mutations that favor chronic HIV-1 infection may be detrimental to transmission dynamics; nevertheless, mutated viruses do transmit, which has important treatment implications.

HIV drug resistance: Within-host development and between-host spread

Among the HIV-1 mutants that can transmit between hosts, drug resistance is one problematic viral characteristic. “In HIV-1, we distinguish acquired drug resistance (ADR) from transmitted drug resistance (TDR). The former, ADR, is drug resistance that occurs in treated individuals, through within-host HIV-1 evolution, which accrues mutations that help it evade ART-mediated selective pressures. On the other hand, TDR is defined as drug resistance that occurs through infection of the host with a viral strain that already harbors drug resistance mutations,” Abecasis elaborated on the distinctions between the two modes of drug resistance.

Abecasis studies trends in ADR and TDR in various populations, including in Europe. In Portugal, Abecasis is involved with BEST HOPE, a cohort of newly diagnosed HIV patients in Portugal. “It is important to monitor trends in ADR and TDR because they are undesirable and problematic,” Abecasis explained of her research interests. “The main cause of ADR is low adherence to treatment by patients. It is possible to mitigate ADR by using antiretroviral drugs that have a higher genetic barrier, meaning they do not induce drug resistance with ease.”

TDR is also problematic, especially for patients that contract an HIV-1 variant harboring resistance to first-line drugs. In this instance, the patient cannot take the recommended first-line therapy because it will be ineffective against the resistant strain. The patient must instead settle on a second-line treatment regimen, which may be more expensive, with more side effects and may also be less convenient in terms of dosage and number of daily pills. “Our work and work by other groups have shown that many TDR mutations have been circulating and transmitted between patients for a long time. Using antiretrovirals with higher genetic barriers should reduce TDR rates. However, we suspect that this is not the case in some parts of Africa where patients’ adherence is very low.”

Furthermore, Abecasis’ research has shed light on risk groups for TDR. “Our transmission cluster approach allows us to identify risk groups for TDR. In a recent survey of 820 patients in Portugal with newly diagnosed HIV-1 infection between 2014 and 2019, we found 89 had TDR. Unexpectedly, TDR was more likely during heterosexual transmission compared to transmission in men who have sex with men, although previous studies found TDR more likely in the latter population.”

Overall, ADR and TDR surveillance can help public health by identifying clusters and reevaluating strategies for encouraging adherence to ART. It can also identify risk groups to target public health campaigns.

Overall, the examples discussed here demonstrate how human host–virus co-evolution occurs by considering both host conditions and viral mutations. Rapid viral evolution generates a variety of mutations that will help the virus flourish or perish in the host, depending on the host conditions. Mutations that help the virus are favored, shaping viral evolution. Changes to the host, for example, when treatments are administered, can exert selective pressures on the virus, altering priorities and favoring different mutations.