As HIV-1 evolves over the course of infection, resistance against antiretrovirals may arise in the absence of drug pressure, especially against receptor and fusion blockers because of the extensive changes observed in the envelope glycoprotein. Here we show that viruses from the chronic phase of disease are significantly less sensitive to CCR5 receptor and fusion blockers compared to early infection variants. Differences in susceptibility to CCR5 antagonists were observed in spite of no demonstrable CXCR4 receptor utilization. No significant sensitivity differences were observed to another entry blocker, soluble CD4, or to reverse transcriptase, protease, or integrase inhibitors. Chronic as compared to early phase variants demonstrated greater replication when passaged in the presence of subinhibitory concentrations of fusion but not CCR5 receptor inhibitors. Fusion antagonist resistance, however, emerged from only one chronic phase virus culture. Because sensitivity to receptor and fusion antagonists is correlated with receptor affinity and fusion capacity, respectively, changes that occur in the envelope glycoprotein over the course of infection confer greater ability to use the CCR5 receptor and increased fusion ability. Our in vitro passage studies suggest that these evolving phenotypes increase the likelihood of resistance against fusion but not CCR5 receptor blockers.

Abstract. Chikungunya virus (CHIKV) is a mosquito-borne pathogen that was only endemic in Africa and south Asia until 2005 and, when the virus spread into the Indian Ocean islands, Europe, and Asia. Autochthonous CHIKV transmission in the Caribbean islands was reported in December of 2013. In Panama, two febrile cases were detected in May of 2014: one traveling from Haiti, and the other traveling from the Dominican Republic. After other imported cases were detected, the first autochthonous case was reported in August of the same year. We detected CHIKV viral RNA and isolated the virus from serum samples. The phylogenetic analysis of the two imported isolates and one autochthonous CHIKV isolate indicated that the viruses belong to the Asian lineage in the Caribbean clade and are related to viruses recently identified in Saint Martin island, British Virgin Islands, China, and the Philippines. Although the circulating CHIKV lineages in the Americas have not yet been described, our results suggest that the Asian lineage is circulating in most American countries reporting autochthonous infection.Chikungunya virus (CHIKV; Alphavirus, Togaviridae) is a mosquito-borne pathogen that is endemic in Africa and some countries in Asia. In 2004, a CHIKV epidemic in costal Kenya was reported, and by 2005 and 2006, CHIKV had spread to the Indian Ocean island of La Reunion as well as Asia, where it caused major epidemics. Several imported cases were reported in Europe and the Americas.1 Three mayor lineages of CHIKV have been described: the east, central and south African (ECSA) lineage, the west African lineage, and the Asian lineage.2 A single mutation in the ECSA strain allowed the emergence of the Indian Ocean outbreak lineage (IOL) because of the increase of viral infectivity, dissemination, and transmission of CHIKV in Aedes albopictus.3,4 The IOL has been related to the explosive CHIKV epidemics in the Indian Ocean and Asia and autochthonous infections in Italy and the south of France as well as several imported cases into the Americas.2,5 Therefore, it was believed that the IOL of CHIKV would reach the Americas, 6 where the two vectors Ae. aegypti and Ae. albopictus have an overlapping distribution 7 and adapt to cause autochthonous infection. Autochthonous CHIKV infections caused by the Asian lineage were reported in December of 2013 on the French island of Saint Martin and spread to several others Caribbean islands and Latin American countries in 2014. 8,9 Here, we report the detection of imported cases of CHIKV in Panama and the establishment of autochthonous infections as well as the results of the genetic characterization of the CHIKV viral strains.On May 13 and 14, 2014, two suspected cases of Chikungunya fever were detected in two public medical facilities in Panama City, Panama. The first patient (256114) was a 23-yearold male with the following travel history: Brazil to Haiti to Panama to Brazil. The day before his travel to Haiti from Rio de Janeiro (May 6), he presented fever, myalgia, and general malaise; he ...

BackgroundChikungunya virus (CHIKV) typically causes explosive epidemics of fever, rash and polyarthralgia after its introduction into naïve populations. Since its introduction in Panama in May of 2014, few autochthonous cases have been reported; most of them were found within limited outbreaks in Panama City in 2014 and Puerto Obaldia town, near the Caribbean border with Colombia in 2015. In order to confirm that Panama had few CHIKV cases compared with neighboring countries, we perform an epidemiological analysis of chikungunya cases reported from May 2014 to July 2015. Moreover, to understand this paucity of confirmed CHIKV cases, a vectorial analysis in the counties where these cases were reported was performed.MethodsChikungunya cases were identified at medical centers and notified to health authorities. Sera samples were analyzed at Gorgas Memorial Institute for viral RNA and CHIKV-specific antibody detection.ResultsA total of 413 suspected cases of CHIKV infections were reported, with incidence rates of 0.5 and 0.7 per 100,000 inhabitants in 2014 and 2015, respectively. During this period, 38.6% of CHIKV cases were autochthonous with rash and polyarthralgia as predominant symptoms. CHIKV and DENV incidence ratios were 1:306 and 1:34, respectively. A phylogenetic analysis of E1/E2 genomic segment indicates that the outbreak strains belong to the Asian genotype and cluster together with CHIKV isolates from other American countries during the same period. Statistical analysis of the National Vector Control program at the district level shows low and medium vector infestation level for most of the counties with CHIKV cases. This index was lower than for neighboring countries.ConclusionsPrevious training of clinical, laboratory and vector workers allowed a good caption and detection of the chikungunya cases and fast intervention. It is possible that low/medium vector infestation level could explain in part the paucity of chikungunya infections in Panama.

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Dengue virus (DENV) is the most prevalent mosquito-borne virus in the world and a major cause of morbidity in the tropics and subtropics. Upregulation of HLA class I molecules has long been considered a feature of DENV infection, yet this has not been evaluated in the setting of natural infection. Natural killer (NK) cells, an innate immune cell subset critical for mounting an early response to viral infection, are inhibited by self HLA class I, suggesting that upregulation of HLA class I during DENV infection could dampen the NK cell response. Here we addressed whether upregulation of HLA class I molecules occurs during in vivo DENV infection and, if so, whether this suppresses the NK cell response. We found that HLA class I expression was indeed upregulated during acute DENV infection across multiple cell lineages in vivo . To better understand the role of HLA class I upregulation, we infected primary human monocytes, a major target of DENV infection, in vitro . Upregulation of total HLA class I is dependent on active viral replication and is mediated in part by cytokines and other soluble factors induced by infection, while upregulation of HLA-E occurs in the presence of replication-incompetent virus. Importantly, blocking DENV-infected monocytes with a pan-HLA class I Fab nearly doubles the frequency of degranulating NK cells, while blocking HLA-E does not significantly improve the NK cell response. These findings demonstrate that upregulation of HLA class I during DENV infection suppresses the NK cell response, potentially contributing to disease pathogenesis.

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Zika virus (ZIKV) was first detected in the Americas in Brazil in 2015, with a rapid spread to surrounding countries. In Panama, the outbreak began in November 2015 in an indigenous community located on the Caribbean side of the country. Zika virus is typically associated with a diffuse rash, fever, and conjunctivitis. It can rarely cause neurologic manifestations, most commonly microcephaly and Guillain-Barré syndrome. Encephalitis and acute encephalomyelitis are known complications, but ZIKV-associated cerebellitis has yet to be reported in the literature. Herein, we report a case of cerebellitis in a patient infected with ZIKV. This patient developed severe frontal headache and vertigo on the third day of illness, and dysarthria and ataxia on the fifth day. After 1 week of hospitalization, the patient completely recovered. The laboratory serological diagnosis was complicated because of the detection of antibodies against dengue, suggesting a secondary flavivirus infection.