DETERMINATION OF THYROID HORMONAL LEVELS IN HIV POSITIVE INDIVIDUALS IN NSUKKA COMMUNITY OF SOUTH EASTERN NIGERIA

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ABSTRACT

This study assessed the levels of cluster determinant 4 (CD4+) cell, total protein, triacylglycerol (TAG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), thyroid stimulating hormone (TSH) and  thyroxine (T4), of one hundred (100) subjects of which twenty-four (24) were healthy subjects which represented normal control (Group1), twenty-eight (28) were HIV-positive subjects who were on treatment with administration of antiretroviral therapy (ART) as Group 2 and forty-eight (48) were HIV- positive subjects who were not on treatment with antiretroviral therapy (NART) (Group 3) and

also to correlate the variation in total protein and lipid profile with the CD4+ cell count for each

of the study groups. Within each of the study groups, subjects were further grouped based on age range i.e. 10-30/yrs, 31-50/yrs and 51-70/yrs irrespective of gender. Blood samples of subjects from Bishop Shanahan hospital, Nsukka were collected for this study. The CD4+ cell count, total protein, TAG, TC, HDL-C, LDL-C, TSH and T4 of group 1 were 1144.63±46.21 cells/µL,

7.09±0.21    g/dL,     117.50±8.85    mg/dL,     193.41±24.76    mg/dL,     54.34±8.29     mg/dL,

112.76±22.08mg/dL,  0.35±0.17  µIU/ml  and  14.91±2.47  ng/ml  respectively;  group  2  were

417.75±45.39 cells/µL, 6.99±0.12 g/dL, 130.01±9.04 mg/dL, 158.42±26.31mg/dL, 39.50±15.45 mg/dL, 96.54±29.76 mg/dL, 0.30±0.13 µIU/ml and 14.55±1.48  ng/ml respectively while those of group 3  were 409.73±28.59 cells/µL,  6.93±0.14 g/dL, 129.90±9.01mg/dL, 156.15±30.61 mg/dL,  41.93±16.95  mg/dL,  88.13±26.79 mg/dL,  0.32±0.19  µIU/ml and  14.39±1.97 ng/ml respectively. The CD4+ cell count were found to be significantly lower (p< 0.05) in groups 2 and

3 of patients when compared to that of uninfected healthy controls. Total protein concentration

of the study groups were found to be within the normal range of 6.0 – 8.2g/dl. Furthermore, TC, HDL and LDL concentration were found to be significantly lower (p<0.05) in groups 2 and 3 irrespective of therapy except for TAG which was significantly higher (p<0.05) when compared to group 1. Also there was a weak positive correlation between CD4+  cell count and HDL-C among group 2 (ART) subjects. TSH and T4 concentrations were found to be lower in the HIV positive  patients  (groups  2  and  3)  when  compared  to  healthy  controls  (group  1).  Again,

concentration of TAG, TC, HDL and LDL fluctuated among the various age groups with no definite pattern. Conclusion from this study shows an alteration of lipid profile in HIV-positive patients irrespective of therapy which could be attributed to low CD4+  cell counts. It was also observed that total protein may not be useful as a marker of HIV infection since values obtained were within the normal range. Conditions of individuals with HIV infection may be attributed to hypothyroidism since TSH concentration is lower when compared to the healthy uninfected controls.

ABSTRACT

This study assessed the levels of cluster determinant 4 (CD4+) cell, total protein, triacylglycerol (TAG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), thyroid stimulating hormone (TSH) and  thyroxine (T4), of one hundred (100) subjects of which twenty-four (24) were healthy subjects which represented normal control (Group1), twenty-eight (28) were HIV-positive subjects who were on treatment with administration of antiretroviral therapy (ART) as Group 2 and forty-eight (48) were HIV- positive subjects who were not on treatment with antiretroviral therapy (NART) (Group 3) and

also to correlate the variation in total protein and lipid profile with the CD4+ cell count for each

of the study groups. Within each of the study groups, subjects were further grouped based on age range i.e. 10-30/yrs, 31-50/yrs and 51-70/yrs irrespective of gender. Blood samples of subjects from Bishop Shanahan hospital, Nsukka were collected for this study. The CD4+ cell count, total protein, TAG, TC, HDL-C, LDL-C, TSH and T4 of group 1 were 1144.63±46.21 cells/µL,

7.09±0.21    g/dL,     117.50±8.85    mg/dL,     193.41±24.76    mg/dL,     54.34±8.29     mg/dL,

112.76±22.08mg/dL,  0.35±0.17  µIU/ml  and  14.91±2.47  ng/ml  respectively;  group  2  were

417.75±45.39 cells/µL, 6.99±0.12 g/dL, 130.01±9.04 mg/dL, 158.42±26.31mg/dL, 39.50±15.45 mg/dL, 96.54±29.76 mg/dL, 0.30±0.13 µIU/ml and 14.55±1.48  ng/ml respectively while those of group 3  were 409.73±28.59 cells/µL,  6.93±0.14 g/dL, 129.90±9.01mg/dL, 156.15±30.61 mg/dL,  41.93±16.95  mg/dL,  88.13±26.79 mg/dL,  0.32±0.19  µIU/ml and  14.39±1.97 ng/ml respectively. The CD4+ cell count were found to be significantly lower (p< 0.05) in groups 2 and

3 of patients when compared to that of uninfected healthy controls. Total protein concentration

of the study groups were found to be within the normal range of 6.0 – 8.2g/dl. Furthermore, TC, HDL and LDL concentration were found to be significantly lower (p<0.05) in groups 2 and 3 irrespective of therapy except for TAG which was significantly higher (p<0.05) when compared to group 1. Also there was a weak positive correlation between CD4+  cell count and HDL-C among group 2 (ART) subjects. TSH and T4 concentrations were found to be lower in the HIV positive  patients  (groups  2  and  3)  when  compared  to  healthy  controls  (group  1).  Again,

concentration of TAG, TC, HDL and LDL fluctuated among the various age groups with no definite pattern. Conclusion from this study shows an alteration of lipid profile in HIV-positive patients irrespective of therapy which could be attributed to low CD4+  cell counts. It was also observed that total protein may not be useful as a marker of HIV infection since values obtained were within the normal range. Conditions of individuals with HIV infection may be attributed to hypothyroidism since TSH concentration is lower when compared to the healthy uninfected controls

CHAPTER ONE

INTRODUCTION

The acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused  by infection with a  retrovirus known as the  human immunodeficiency virus (HIV) (Sepkowitz, 2001). The virus breaks down the body’s immune system, infects CD4+ cells initially

and progressively leads to AIDS (Rasool et al., 2008). The CD4+ cells also known as T-helper

cells are a type of white blood cells that play important roles in the immune system. CD4+ cells are made in the spleen, lymph nodes, and thymus gland, which are part of the lymph or infection- fighting system. These helper cells move throughout the body, helping to organize the immune

+

system’s response to bacteria, fungi and viruses (Fevrier et al., 2011). CD4
cell counts alongside

other parameters are of central importance in the monitoring of immune function (Aina et al.,

2005). The CD4+ lymphocyte is the primary target of HIV infection because of the affinity of the virus to the CD4+ surface marker and also its ability to enter CD4+ cells and become part of them. As the cells multiply to fight infection, they also make more copies of HIV (Khiangte et al.,

2007).

Infection with HIV leads to a progressive impairment of cellular functions, characterized by a gradual decline in peripheral blood CD4+   lymphocyte levels  which results in an increasing susceptibility to a wide variety of opportunistic, viral, bacterial, protozoal, and fungal infections (Khiangte et al., 2007). Increasing experience with this syndrome has led to the recognition of a variety of HIV related endocrine disorders that occur during both the early and late stages of the disease. Endocrine function may be altered in individuals with Human Immunodeficiency virus (HIV) infection because of the possible relationship between the immune and endocrine systems, direct involvement of the glands by the HIV itself, opportunistic infections and malignancies

(Raffi et  al., 1991). Among these  disorders, a high prevalence of abnormalities in thyroid function tests is reported (Lambert et al., 1990).

Thyroid disorders are some of the most common endocrine disorders encountered in clinical practice (DeRuiter, 2001). Thyroid disorders found in HIV include sick euthyroid syndrome, subclinical hypothyroidism (3.5-12.2%) (Madeddu et al., 2006), Grave’s disease due to the

immune reconstitution syndrome  (Knysz  et  al.,  2006)  and  thyroiditis due  to  Cryptococcus neoformans, Pneumocystis jiroveci, and visceral leishmaniasis (Selimeyer and Grunfeld, 2006). Thyroid function may also be disturbed by lymphoma and Kaposis sarcoma. Thyroid hormone was speculated since hypothyroidism caused oedema of the uterine tube which disposes the victim to susceptibility to non-specific infection, HIV infection inclusive (Amadi et al., 2007). The primary function of thyroid hormone is to regulate basal metabolism, which is what occurs during rest and not exercise. Besides factors such as decreased food intake and malabsorption, HIV infection is typically associated with adverse metabolic events (Gasparis and Tassiopoulos,

2001). Thyroid hormones (TH) are essential for normal development, differentiation, growth and metabolism of every cell in the body (Feldt-Rasmussen and Rasmussen, 2007). Abnormalities in protein, glucose and lipid metabolism have been elicited in HIV infected patients since recognition of the AIDS epidemic (Salas-Salvado and Garcia-Lorda, 2001). Most of these HIV- associated abnormalities are thought to be indirect effects of viral replication and to be mediated through HIV-induced immune activation (Serpa et al., 2010). Report show elevation of serum thyroid stimulating hormone (TSH) and thyrotropin-releasing hormone (TBG) concentration  in conjunction with low free thyroxin (FT4) that occurs frequently and correlates with CD4+  cell depletion  in  AIDS  persons.  In  patients  with  advanced  HIV  disease,  a  variety of systemic opportunistic conditions that infect or infiltrate the thyroid can decrease or increase thyroxine (T4) secretion (Pearce, 2006). These infiltrating conditions lead to destructive thyroiditis, which is usually accompanied by neck pain, thyroid enlargement and increased thyroxine release (Lima et al., 1998). This study attempts to examine the varieties in serum thyroid hormonal levels,

changes in lipid, CD4+ T cell counts, and total serum protein of HIV positive individuals who are

on Antiretroviral therapy (ART) with those who are not on Antiretroviral therapy and HIV- negative controls in Nsukka Community of South Eastern Nigeria.

1.1 Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) Acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by infection with human immunodeficiency virus (HIV) (Sepkowitz, 2001). The presence of this virus  progressively reduces  the  effectiveness  of  the  immune  system  and  leaves  its  victim susceptible to opportunistic infections and tumours. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood,

semen, vaginal fluid, preseminal fluid, and breast milk.  This transmission can involve anal or vaginal sex, blood transfusion, contaminated hypodermic-needles, exchange between mother and baby during pregnancy, childbirth, or breastfeeding, or other exposure to one of the above bodily fluids (Markowitz, 2007).

AIDS is considered a pandemic—a disease outbreak which is present over a large area and is actively spreading (Kallings, 2008). Although treatments for AIDS and HIV infection can slow the course of the disease, there is currently no vaccine or cure. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but these drugs are expensive and routine access to antiretroviral medication is not available in all countries (Pelella, et al., 1998).

1.1.1 Classification of Human Immunodeficiency Virus

HIV-1,  the  causative  agent  of  AIDS  in  human,  belongs  to  the  Lentivirus  genus  of  the Retroviridae family. This family has a unique enzyme called reverse transcriptase that converts viral RNA to DNA upon viral entry into the cell (ICTV, 2002).

Lentivirus has  many morphologies and  biological properties. Many species are  infected by Lentivirus, which are characteristically responsible for long-duration illness with a long incubation period (Levy, 1993). Lentivirus is transmitted as single-stranded, enveloped RNA virus. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally encoded reverse transcriptase that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded integrase and host co-factor (Smith and Daniel, 2006). Once integrated, the virus may become latent, allowing the virus and its  host  cell  to  avoid  detection  by  the  immune  system.  Alternatively,  the  virus  may  be transcribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new virus particles that begin the replication cycle again (Smith and Daniel, 2006).

1.1.2 Characterization of Human Immunodeficiency Virus

Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 was initially discovered and termed both LAV and HTLV-111. HIV-1 is easily transmitted. It is more virulent, more infective and is the cause of the majority of HIV infections globally. HIV-1 can be divided into

three subgroups: HIV-1-M, HIV-1-N and HIV-1-O, of which HIV-1-M is the most prevalent and has spread around the world (Gilbert et al., 2003; Nicki et al., 2010).  HIV-2 was isolated from AIDS patients in West Africa. HIV-2 is initially less virulent and is confined largely to countries in West Africa; e.g. Senegal, Ghana, Liberia and the Ivory Coast (Fisher and Madden, 2011). The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of those exposed to HIV-2 will be infected per exposure. HIV-2 causes a similar illness to HIV-1 but is less aggressive and restricted mainly to Western Africa (Reeves and Doms, 2002; Nicki et al., 2010).

1.1.3 Origin of Human Immunodeficiency Virus

Genetic research indicates that HIV originated in west-central Africa during the early twentieth century (Sharp and  Hahn,  2011).  HIV-1 appears to  have  originated in southern Cameroon through the evolution of SIV (cpz), a simian immunodeficiency virus (SIV) that infects wild chimpanzees. The closest  relative of HIV-2 is  SIV (smm), a virus of the sooty mangabey (Cercocebus atys atys), an Old World monkey living in littoral West Africa (Reeves and Doms,

2002). However, SIV is a weak virus which is typically suppressed by the human immune system within weeks of infection. It is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough time to mutate into HIV (Marx et al., 2001). AIDS was first recognized by the Centers for Disease Control and Prevention (CDC) in 1981 among homosexual men in the United States (UNAIDS and WHO,

2003). By 1983, the etiological agent, the human immunodeficiency virus (HIV), was identified (UNAIDS and WHO, 2003; Gallo, 2006). Since its discovery, AIDS has caused nearly 30 million deaths (as of 2009) (Global Report Fact Sheet, UNAIDS, 2009).

1.1.4 Structure of Human Immunodeficiency Virus

Fig. 1: Structure of human immunodeficiency virus (HIV) showing viral genes, proteins, nucleic acid and viral enzymes (Study material: London School of Hygiene and Tropical Medicine).

Matured virion of HIV is roughly spherical with a diameter of about 120nm. It is around 60 times smaller than a red blood cell, yet large for a virus (McGovern et al., 2002). It has a lipid membrane lined by a matrix protein that is studded with glycoprotein (gp) 120 and gp41 spikes surrounding a cone-shaped protein core (Nicki et al., 2010). This core is composed of two copies of positive single-stranded RNA that codes for the virus’s nine genes enclosed by a conical capsid composed of 2000 copies of the viral protein p24 (HSC, 2008). The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle (HSC,2008).

Surrounding the capsid is the viral envelope that is composed of a lipid bilayer membrane, formed from the cellular membrane of the host cell during budding of the newly formed virus particle. Embedded within the viral envelope are host-cell proteins such as the major histocompatibility complex (MHC) antigens and actin along with about 70 copies of a complex HIV protein that protrudes through the surface of the virus particle (Shehu-Xhilage and Oelrichs, 2004). This protein, known as Env (envelope protein) which is the most valuable component of

HIV, consists of two non-covalently linked membrane proteins: a cap made of three molecules called glycoprotein (gp) 120, the outer envelope protein and a stem consisting of three gp41 molecules, the transmembrane protein   that anchors the glycoprotein complex to the surface of the virion (Chan et al., 1997; Shehu-Xhilaga and Oelrichs, 2004). This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle (Chan et al.,1997).

1.1.5 Genome of Human Immunodeficiency Virus

Genomes of all single-stranded RNA viruses contain internal structures fundamental to viral replication and host defense evasion. Important viral RNA structures include ribosome entry sites, packaging signals, pseudoknots, transfer RNA mimics, ribosomal frame shifts, motifs, and cis-regulatory elements  (Cann,  2005).  In  the  human  immunodeficiency virus  (HIV),  RNA structures activate transcription, initiate reverse transcription, facilitate genomic dimerization, direct HIV packaging, manipulate reading frames, regulate RNA nuclear export, signal polyadenylation, and interact with viral and host proteins (Goff, 2007).

The RNA genome consists of at least seven structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS), and nine genes (gag, pol, env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat, env and rev), encoding 19 proteins. Three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles (HSC,

2008). The six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease (Shehu-Xhilaga and Oelrichs, 2004). The three structural proteins are Gag, Pol and Env polyproteins which are subsequently proteolyzed into individual proteins:

(1) The four Gag proteins, MA (matrix), CA (capsid), NC (nucleocapsid) and p6,

(2) The two Env proteins, SU (surface or gp120) and TM (transmembrane or gp41) are structural components that make up the core of the virion and outer membrane envelope; and

(3) The three Pol proteins, PR (protease), RT (reverse transcriptase) and IN (integrase), provide essential enzymatic functions and are also encapsulated within the particle (Dragic, 2001 and Levin et al., 2005).

The two Tat proteins (p16 and p14) are transcriptional transactivators for the LTR promoter acting by binding the TAR RNA element. The Rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the RRE RNA element. The Vif protein (p23) prevents the action of APOBEC3G (a cell protein that deaminates DNA: RNA hybrids and/or interferes with the Pol protein). The Vpr protein (p14) arrests cell division at G2/M. The Nef

protein (p27) down-regulates CD4+  (the major viral receptor), as well as the MHC class I and

class II molecules (Schwartz et al., 199; Garcia and Miller 1991)

Nef also interacts with SH3 domains. The Vpu protein (p16) influences the release of new virus particles from infected cells (HSC, 2008). The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell. The Psi element is involved in viral genome packaging and recognized by Gag and Rev Proteins. The SLIP element (TTTTTT) is involved in the frame shift in the Gag-Pol reading frame required to make functional Pol (HSC, 2008).

1.1.6 Life Cycle of Human Immunodeficiency Virus (HIV)

The life cycle of HIV comprises the series of events that begins with the attachment of the virus to the CD4+ receptor on the host cell surface, and ends with the production of new viral particles that bud off from the new host cell. This process is shown in Fig. 2.

1.1.6.1 HIV binding and entry

The first step of the HIV life cycle is attachment to the host cell. This process begins when the gp120 protein on the viral surface binds to a CD4+  receptor on the host cell surface by a mechanism that  involves conformational changes in both the CD4+  receptor and the gp120 protein (Bryntesson, 2009).The interaction requires the recognition of two host-cell surface- receptor proteins by the viral gp120 envelope protein. The presence or absence of these cognate

cellular proteins restricts the range of host-cell types that are susceptible to infection by a strain of HIV. The first co-receptor described was the CD4+ protein which is present predominantly on cells of the T lymphocyte and macrophage lineages. The distribution of CD4+ receptors has been thought to restrict HIV susceptibility to cells of the lymphocyte, monocyte/macrophage and other CD4+-expressing lineages, although more recent studies have shown efficient viral entry into

cells not expressing CD4+ (Borsetti et al., 2000; Liu et al., 2000). Subsequently, the requirement of a second   co-receptor for viral entry was recognised. This function may be performed by a range  of  proteins  within  the  class  of  seven-transmembrane  receptors,  although  the  most important are CCR5 (CC chemokine receptor 5) and CXCR4 (CXC chemokine receptor 4). The in vivo significance of entry via these minor co-receptors, however, remains unclear (Shehu Xhilage and Oelrichs, 2004). The importance of co-receptor binding for a successful HIV-1 infection is underlined by the findings that HIV-1 infectivity is compromised in individuals that

harbor mutant (not functioning) CCR5 proteins, and that agents that bind to CCR5 and CXCR4 (and thus block HIV-1 from binding to these receptors) reduce viral infectivity (Berger et al.,

1999; Carrington et al., 1999; Schols, 2004). In general, viral strains that bind to CCR5 (R5 strains) infect macrophages and T cells, and are characterised by less aggressive growth in vitro. Strains that recognise CXCR4 (X4 strains), by contrast, infect only T cells and T cell lines (Cho et al., 1998)

After HIV gp120 binds to CD4+  and the co-receptor, a conformational change in gp41 causes insertion of the N-terminal hydrophobic fusion-peptide region into the target-cell membrane (Fouchier and Malim, 1999). This insertion results in membrane fusion and the entry of the viral particle contents into the cytoplasm, a process critically dependent upon interactions between the N- and C-terminal regions of the gp41 ectodomain. This intra-protein interaction presents a target for pharmacological intervention by short peptides, such as T-20 (enfuviritide), that mimic the structure of the conserved C-terminal region of gp41 (Kilby et al., 1998). The genetic information of HIV is contained within an RNA genome. After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, is injected into the cell. During the microtubule-based transport to the nucleus, the viral single-stranded RNA is first reverse transcribed into single-stranded DNA that is then further transcribed to double-stranded DNA for integration into the host-cell genome (Chan et al., 1997 and Fouchier and Malim, 1999).



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